Adjuvant therapy options following curative treatment of hepatocellular carcinoma: A systematic review of randomized trials

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EJSO 38 (2012) 286e295

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Adjuvant therapy options following curative treatment of hepatocellular carcinoma: A systematic review of randomized trials J.-H. Zhong a,c, H. Li b,c, L.-Q. Li a,*, X.-M. You a, Y. Zhang a, Y.-N. Zhao a, J.-Y. Liu a, B.-D. Xiang a, G.-B. Wu a a

Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning 530021, PR China b Ultrasound Department, Tumor Hospital of Guangxi Medical University, Nanning 530021, PR China Accepted 5 January 2012 Available online 24 January 2012

Abstract Aims: Numerous postoperative therapies for preventing recurrence of hepatocellular carcinoma (HCC) have been reported, but their efficacy remains controversial and knowledge about adverse effects is limited. A systematic review of randomized controlled trials (RCTs) was performed to gain a comprehensive picture of the efficacy and risks of these therapies. Methods: MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. Results: A total of 2989 patients from 28 RCTs involving 10 postoperative therapies were included. For interferon therapy, the estimated RR for the 2-year recurrence rate was 0.84 (95% CI 0.73e0.97, P ¼ 0.02) and the overall survival (OS) was 1.15 (95% CI 1.07e1.22, P < 0.001). Postoperative therapy with the vitamin K2 analog did not lead to a significant reduction in the 1-year recurrence rate, with a pooled RR of 0.60 (95% CI 0.28e1.27, P ¼ 0.18). However, it did slightly improve the 1-year OS, with a pooled RR of 1.03 (95% CI 1.00e1.05, P ¼ 0.03). Transarterial chemotherapy with or without embolization, adoptive immunotherapy and heparanase inhibitor PI-88 therapy may delay tumor recurrence. The effects of acyclic retinoid, lipiodol-iodine-131 and tumor vaccine treatment were promising but require further study. All postoperative therapies except interferon administered intramuscularly were well tolerated by the majority of patients. Conclusions: Use of adjuvant interferon is definitely associated with an increase in OS. Postoperative therapies involving acyclic retinoid, lipidol-iodine-131, or tumor vaccine may improve the OS of patients with HCC after curative treatment. Ó 2012 Elsevier Ltd. All rights reserved. Keywords: Adverse effects; Hepatocellular carcinoma; Postoperative; Overall survival; Systematic review

Introduction Hepatocellular carcinoma (HCC), a malignancy with poor prognosis, has a heterogeneous composition with multiple variables that vary from region to region.1 The incidence of HCC is increasing in many countries.2,3 Resection and ablation remain the primary treatments for HCC. However, even after curative resection or ablation, recurrence is common and is, in fact, the main cause of patient deaths. Consequently, adequate adjuvant and/or chemopreventive therapy is needed to improve survival. * Corresponding author. Tel.: þ86 771 5330968; fax: þ86 771 5312000. E-mail address: [email protected] (L.-Q. Li). c Both authors contributed equally to this work. 0748-7983/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2012.01.006

Various types of postoperative therapies have been reported for HCC patients following curative treatment. However, benefits of adjuvant or chemopreventive therapy have not been definitively demonstrated.4 Several randomized controlled trials (RCTs) have reported inconsistent or even contradictory data, and available systematic reviews have included only a few RCTs or have explored only one form of adjuvant therapy. In addition, most of the systematic reviews on this topic have not assessed the adverse effects of adjuvant or chemopreventive therapies. Here we describe a large-scale systematic review intended to provide a more comprehensive analysis to help identify the most suitable postoperative therapy for patients with HCC after curative treatments.

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Methods

Data extraction

Identification of trials

Two reviewers independently extracted data concerning author details, methodological quality, number of patients, patient characteristics, interventions and outcomes. Discrepancies were resolved by consensus. When multiple publications of the same trial were identified, data were extracted from the multiple publications and reported as a single trial.

The electronic databases of MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Studies comparing curative treatment alone with curative treatment followed by postoperative therapy were identified using the following key words: hepatocellular carcinoma, hepatic tumor, liver tumor, postoperative, adjuvant, chemopreventive. In order to include all possible studies, the search was not limited to controlled or randomized trials. Manual search of relevant references and review articles was also performed. There were no language restrictions. Studies identified by the search were screened independently by two reviewers (J-H Z and Y Z). Any disagreements were arbitrated by a third reviewer (L-Q L). In the end, only RCTs were included. Types of patients and interventions Only RCTs that assessed the effect of adjuvant or chemoprevention therapies for HCC after curative treatment (resection and local ablation) were included. Hepatic resection was considered curative only when the histological resection margin was clear. Local ablation was considered curative when the postoperative computed tomography scan showed no residual tumors at 1 month after therapy. Patients in the control arm received hepatic resection or local ablation alone. Studies examining liver metastases were excluded, as were studies that assessed the effect of neoadjuvant therapy with or without adjuvant therapy. Types of outcome measures The primary outcomes evaluated in this review were overall survival (OS), disease-free survival (DFS) and recurrence rate. The secondary outcome was incidence of adverse events attributable to the use of adjuvant or chemopreventive therapies. Quality assessment Two reviewers independently evaluated the quality of each retrieved trial according to the method described in the Cochrane Handbook for Systematic Reviews of Interventions. Sequence generation of randomization, allocation concealment, blinding of patients and personnel and blinding of outcome assessment were evaluated. Trials were considered to be of high quality if they reported the method of randomization in detail and used allocation concealment or performed intention-to-treat analysis, of moderate quality if they reported either the method of randomization in detail or used allocation concealment but not both, and of low quality if they neither reported the method of randomization in detail nor used allocation concealment.

Statistical analysis The statistical analysis was done using the software package RevMan 5.1. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes. Homogeneity between trials was analyzed by the c2-test with significance set at P > 0.1, and the extent of heterogeneity was assessed by calculating I2. The point estimate of the RR was considered statistically significant at the P < 0.05 level if the 95% CI did not include 1. Data from each study found to have heterogeneity or to have a limited number of patients were collected and discussed in a narrative review. Publication bias Asymmetry of a funnel plot of trial size against treatment effect was used to assess the risk of bias.5 Results Selection of studies Our search yielded 676 clinical studies relevant to adjuvant or chemopreventive therapy for HCC. Fourteen studies were excluded because some patients had received neoadjuvant therapies, resection may not have been curative, or a real control group (no adjuvant therapy) was not included. In the end, 28 RCTs involving 2989 patients were included6e33 (Fig. 1). In 15 of the studies, intention-to-treat analysis was performed. The sample size varied from 20 to 548 patients. The main characteristics of the 28 studies are shown in Table 1. The funnel plot showed no evidence of publication bias. Methodological quality was high in 20 studies,6e15,17,19,22,24e28,31,33 moderate in 4 studies18,23,29,32 and low in the remaining 4 studies.16,20,21,30 Characteristics and effects of interferon (IFN) treatment Eight RCTs examined postoperative IFN treatment.6e13 Patients in the treatment group received 3e10 million units of IFN intramuscularly, and the IFN treatment schedule varied in different studies. Treatment duration ranged from 4 months to 3 years. Since the follow-up ranged widely from 25 months12 to more than 7 years,11 only the 2-year

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676 potentially relevant articles

Citations excluded after screening titles and abstracts n = 606 81 reviews 35 meta -analyses 68 case -control studies 92 single -arm studies 90 case reports 240 observational studies Studies retrieved for detailed evaluation n = 70 Citations excluded after full assessment n = 42 Duplicate n = 28 Neoadjuvant therapy n=4 Resection may not have been curative n=5 No real control arm n=5

28 randomized controlled trials included in analysis Figure 1. Process for selecting randomized controlled trials for this systematic review.

tumor recurrence rate and 2-year OS were calculated in the meta-analysis. Adjuvant IFN therapy significantly reduced the risk of 2year recurrence, with a pooled RR of 0.84 (95% CI 0.73e0.97, P ¼ 0.02) and without heterogeneity (P ¼ 0.36, I2 ¼ 9%) (Fig. 2). In all the IFN studies except Ref. 12, adjuvant IFN therapy improved 2-year OS, with a pooled RR of 1.15 (95% CI 1.07e1.22, P < 0.001) and significant heterogeneity (P ¼ 0.08, I2 ¼ 46%) (Fig. 3). Characteristics and effects of vitamin K2 (VK2) analog treatment Five RCTs14e18 assessed the effect of VK2 analog on recurrence rate and OS in HCC patients. Patients in the treatment group received oral doses of 45 or 90 mg/d VK2 analog. Because of incomplete follow-up data across studies, only the 1-year tumor recurrence and 1-year OS were calculated in the meta-analysis. VK2 analog therapy was not associated with a significant reduction in recurrence, with a pooled RR of 0.60 (95% CI 0.28e1.27, P ¼ 0.18) and statistical heterogeneity (P ¼ 0.004, I2 ¼ 74%) using a random-effect model. All the studies reported survival rates,14e18 and no heterogeneity in OS was found among the trials (P ¼ 0.67, I2 ¼ 0%). VK2 analog therapy significantly improved 1-year OS, with a pooled RR of 1.03 (95% CI 1.00e1.05, P ¼ 0.03) (Fig. 3).

Other postoperative therapies The remaining 15 studies examined the efficacy of postoperative therapy involving acyclic retinoid,19 transarterial chemoembolization (TACE),20e22 transarterial chemotherapy (TAC),23 systemic chemotherapy,24e26 a combination of systemic and transarterial chemotherapy,27 intra-artery iodine-131-labeled lipiodol,28 adoptive immunotherapy (AIT),29e31 autologous tumor vaccination32 and heparanase inhibitor PI-88.33 Due to the diversity of drugs in different studies, meta-analysis could not be performed. The main characteristics and effects of these 15 studies are shown in Tables 1 and 2 and are discussed below. Acyclic retinoid Oral acyclic retinoid may prevent second primary hepatomas by eradicating latent neoplastic clones.34 The 3-year DFS was 63% in the acyclic retinoid group, much higher than the 45% in the control group (P < 0.05).35 The estimated 6-year OS was 74% in the acyclic retinoid group and 46% in the control group (P < 0.05).34 TACE and TAC The study by Izumi and co-workers20 showed that the 3year DFS was higher in the TACE group than in the control group. However, the 3-year OS was similar in both groups. In another study,21 most of the 94 patients had tumors with

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Table 1 Characteristics of included studies comparing curative treatment followed by adjuvant or chemopreventive therapy with curative treatment alone. Study Interferon Chen et al.6 Lo et al.7 Mazzaferro et al.8 Sun et al.9 Lin et al.10 Shiratori et al.11 Ikeda et al.12 Kubo et al.13 Vitamin analog Yoshiji et al.14

Country or region

Sample size (T/C)a

Follow-up

Child-Pugh classification (A/B)

% Cirrhosis

% HBsAgpositive

% Anti-HCVpositive

% Vascular invasion

Taiwan Hong Kong Europe China Taiwan Japan Japan Japan

133/135 40/40 76/74 118/118 20/10 49/25 10/10 15/15

41.8 m >30 m 45 m 36.5 m 27 m (range, 4e53) range, 5.8e8.4 y 25 m w50 m

264/0 NR 140/10 NR 26/2 74/0 NR 23/7

55 48 100 86 93 100 85 50

85 90 47 100 53 0 0 0

24 4 100 0 47 100 100 100

27 41 25 76 NR NR 0 NR

Japan

18/25

35/5

NR

7

77

NR

477/71 44/16 48/13

78 100 NR

11 0 8

83 100 89

NR NR NR

27/18

NR

20

73

NR

NR

NR

14

75

NR

NR NR 90/14 NR

82 77%b 66 NR

16 NR 60 NR

82 NR 86 NR

54 NR 100 NR

138/21 NR 60/0

50 69 67

18 NR 83

72 NR NR

22 1 63

NR

55

85

NR

45

NR

NR

88

NR

5

102/25 69/16 104/46 36/3

80 NR 49 54

76 NR 19 90

NR NR 66 3

46 NR 44 33

162/6

56

73

23

23

T: 36 m C: 48 m Japan 367/181 range, 3e3.5 y Yoshida et al.15 Japan 30/30 NR Kakizaki et al.16 Japan 32/29 T: 28.9 m Mizuta et al.17 C: 27.7 m Japan 21/24 T: 19.5 m Hotta et al.18 C: 16.5 m Japan 44/45 150 m Muto et al.19 Transarterial chemotherapy with or without embolization Japan 23/27 NR Izumi et al.20 China 47/47 NR Li et al.21 China 63/63 NR Peng et al.22 Japan 10/11 NR Ueno et al.23 Systemic chemotherapy (oral) 79/80 4.8 y (range, 0.5e7.9) Hasegawa et al.24 Japan 35/32 NR Yamamoto et al.25 Japan China 30/30 47.5 m (range, 4e65) Xia et al.26 Combination of systemic and transarterial chemotherapy Hong Kong 30/36 28.3 m Lai et al.27 (range, 4.9e77.1) Intra-arterial lipiodol-iodine-131 Hong Kong 21/22 66 m (range, 3e198) Lau et al.28 Immunotherapy China 41/43/43c range, 5e7 y Dong et al.29 30 China 45/40 18 m Weng et al. 76/74 4.4 y (range, 0.2e6.7) Takayama et al.31 Japan China 18/21 15 m (range, 8e28) Kuang et al.32 Heparanase inhibitor PI-88 Taiwan 56/54/58c 48 w Liu et al.33 a b c

Abbreviations: T, treatment group; C, control group; NR, not reported; m, months; w, weeks; y, years. Including palliative resection patients. The study has two treatment groups and one control group.

diameters >5 cm and the 3-year OS was significantly higher in the TACE group. In a third study,22 the TACE group also showed a significantly better 3-year OS. Only one study23 investigated adjuvant TAC versus no therapy. It involved 21 patients with moderate hepatitis and it reported that TAC significantly improved 3-year DFS. Systemic chemotherapy Three studies explored the effects of systemic chemotherapy.24e26 The study by Hasegawa and co-workers24 concluded that oral uraciletegafur did not benefit patients with HCC after curative hepatectomy. In fact, those authors suggested that adjuvant uraciletegafur may lower OS. However, Yamamoto et al.25 drew an opposite conclusion, reporting that 5-year DFS and OS of patients with stage I

disease was higher in the oral carmofur group than in the control group (P < 0.05). Xia et al.26 found that oral capecitabine did improve 5-year DFS, but the authors concluded that it was unlikely to improve OS. Lai et al.27 tested the efficacy of combining systemic and transarterial chemotherapy and found that this approach was associated with more frequent extrahepatic recurrence and worse outcomes. In contrast, Lau et al.28 found that adjuvant iodine-131labeled lipiodol therapy significantly improved 3-, 5- and 7-year DFS and OS. AIT All three studies29e31 exploring the effect of AIT reported significantly longer DFS in the AIT group than in the control group, but similar OS between the groups.

290

J.-H. Zhong et al. / EJSO 38 (2012) 286e295 Interferon Study or Subgroup

Control

Risk Ratio

Events Total Events Total Weight

Risk Ratio

M-H, Fixed, 95% CI

Chen 2005

51

133

55

135

24.8%

0.94 [0.70, 1.27]

Ikeda 2000

0

10

7

10

3.4%

0.07 [0.00, 1.03]

Kubo 2002

5

15

6

15

2.7%

0.83 [0.32, 2.15]

Lin 2003

5

20

6

10

3.6%

0.42 [0.17, 1.04]

Lo 2007

17

40

20

40

9.1%

0.85 [0.53, 1.37]

Mazzaferro 2006

40

76

39

74

18.0%

1.00 [0.74, 1.35]

Shiratori 2003

25

49

17

25

10.2%

0.75 [0.51, 1.10]

Sun 2006

52

118

62

118

28.2%

0.84 [0.64, 1.09]

427 100.0%

0.84 [0.73, 0.97]

Total (95% CI) Total events

461 195

M-H, Fixed, 95% CI

212

Heterogeneity: Chi² = 7.68, df = 7 (P = 0.36); I² = 9%

0.2 0.5 1 2 5 Favours interferon Favours control

Test for overall effect: Z = 2.35 (P = 0.02)

Figure 2. Meta-analysis of 2-year tumor recurrence in randomized controlled trials comparing curative treatment plus interferon with curative treatment alone for hepatocellular carcinoma. CI, confidence interval.

One study evaluated the effect of autologous tumor vaccination for conferring protective immunity against HCC recurrence.32 Both the DFS and OS were significantly better in the tumor vaccine group than in the control group, and patients with low tumor burdens showed particularly strong benefits from the tumor vaccination.32

in the untreated group (P ¼ 0.07). Receiving 160 mg/ d PI-88 led to a 78% improvement in time to recurrence compared with the control group. However, in patients receiving 250 mg/d PI-88, the time to recurrence was similar to that of the control group. Adverse effects of postoperative therapies

Heparanase inhibitor PI-88 Liu and co-workers33 explored the effect of heparanase inhibitor PI-88 in a Phase II clinical trial. They noted that DFS was marginally higher in the 160 mg/d group than Treated Study or Subgroup

Control

IFN The most common adverse effects after the initial IFN injection were fever, chills, fatigue, myalgia, headache, Risk Ratio

Events Total Events Total Weight

M-H, Fixed, 95% CI

Risk Ratio M-H, Fixed, 95% CI

1.2.1 Interferon (2-year overall survival) Chen 2005

120

133

119

135

36.7%

1.02 [0.94, 1.11]

Kubo 2002

15

15

13

15

4.2%

1.15 [0.91, 1.44]

Lin 2003

16

20

5

10

2.1%

1.60 [0.83, 3.09]

Lo 2007

35

40

27

40

8.4%

1.30 [1.01, 1.66]

Mazzaferro 2006

59

76

51

74

16.0%

1.13 [0.93, 1.37]

Shiratori 2003

47

49

22

25

9.0%

1.09 [0.93, 1.27]

Sun 2006 Subtotal (95% CI)

97

118 451

76

118 23.6% 417 100.0%

1.28 [1.09, 1.50] 1.15 [1.07, 1.22]

Total events

313

389

Heterogeneity: Chi² = 11.20, df = 6 (P = 0.08); I² = 46% Test for overall effect: Z = 4.04 (P < 0.0001) 1.2.2 Vitamin K2 analog (1-year overall survival) Hota 2007

21

21

21

24

6.0%

1.14 [0.96, 1.35]

Kakizaki 2007

30

30

29

30

8.7%

1.03 [0.94, 1.13]

Mizuta 2006

32

32

28

29

8.8%

1.04 [0.95, 1.14]

365

367

177

181

70.1%

1.02 [0.99, 1.04]

18

18 468

25

6.4% 25 289 100.0%

1.00 [0.91, 1.10] 1.03 [1.00, 1.05]

Yoshida 2011 Yoshiji 2009 Subtotal (95% CI) Total events

466

280

Heterogeneity: Chi² = 2.34, df = 4 (P = 0.67); I² = 0% Test for overall effect: Z = 2.19 (P = 0.03)

0.5 0.7 1 1.5 2 Favours control Favours experimental Test for subgroup differences: Chi² = 9.50, df = 1 (P = 0.002), I² = 89.5%

Figure 3. Meta-analysis of overall survival in randomized controlled trials comparing curative treatment plus interferon or vitamin K2 analog with curative treatment alone for hepatocellular carcinoma. CI, confidence interval.

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Table 2 Interventions and results of included randomized trials assessing postoperative therapies for patients with hepatocellular carcinoma after curative interventions. Study

Drugs and dose

Interferon (intramuscularly) Interferon-a (5 MIU/m2) 5 times weekly Chen et al.6 for 4 weeks, then 3 times weekly for 48 weeks Interferon-a (10 MIU/m2) 3 times weekly Lo et al.7 for 16 weeks Mazzaferro et al.8 Interferon-a (3 MIU/m2) 3 times weekly for 48 weeks Interferon-a (3 MIU/m2) 2 times weekly for 2 weeks, Sun et al.9 then 5 MIU/m2 3 times weekly for 72 weeks Interferon-a (3 MIU/m2) 3 times weekly for 96 weeks; Lin et al.10 or daily for 10 days every month for 6 months, then daily for 10 days every 3 months for a further 18 months Shiratori et al.11

Interferon-a (6 MIU/m2) 3 times weekly for 48 weeks

Ikeda et al.12

Interferon-b (6 MIU/m2) 2 times weekly for 36 weeks

Kubo et al.13

Interferon-a (6 MIU/m2) every day for 2 weeks, then 3 times a week for 14 weeks and finally 2 times a week for 88 weeks Vitamin analog (oral) Oral menatetrenone (45 mg/d) for 36 months Yoshiji et al.14

Yoshida et al.15

Oral menatetrenone (45 or 90 mg/d) during the follow-up period

Kakizaki et al.16

Oral menatetrenone (45 mg/d) during the follow-up period

Outcomes

Treatment arm (%)

Control arm (%)

p-value

5-year 5-year 5-year 5-year 5-year 5-year 5-year 1-year rate 4-year rate 5-year rate 5-year 2-year rate 5-year rate 5-year

DFS OS DFS OS DFS DFS OS recurrence

44 75 43 79 24 37 58 25

46 72 38 61 5.8 36 44 40

>0.05 >0.05 >0.05 >0.05 >0.05 >0.05 <0.05 <0.05

recurrence

47

90

<0.05

recurrence

80

92

>0.05

OS recurrence

68 100

48 0

<0.05 <0.05

recurrence

33

80

<0.05

OS

76

45

<0.05

3-year rate 3-year 1-year 1-year

recurrence

61

68

<0.05

OS DFS OS

88 70 97

<0.05 >0.05 >0.05

DFS OS recurrence

89 65 99 (45 mg/d) and 99 (90 mg/d) 39 77.5 64.3

10 66.4 91.6

<0.05 >0.05 <0.05

OS recurrence

87 28.6

64 46.5

>0.05 <0.05

OS DFS OS

100 63 74

81.7 45 46

>0.05 <0.05 <0.05

DFS OS OS

32 56.6 69.5

11.7 53.4 35.1

<0.05 >0.05 <0.05

OS

33.8

17.0

<0.05

DFS

70

22

<0.05

DFS OS DFSa OSa DFS OS

29 58 50 72 46.7 62.5

29 73 19 49 23.3 39.8

>0.05 >0.05 <0.05 <0.05 <0.05 >0.05

DFS OS

18 65

48 64

<0.05 >0.05

DFS OS

74.5 86.4

36 46.3

<0.05 <0.05

3-year 3-year Oral menatetrenone (45 mg/d) during the follow-up period 3-year Mizuta et al.17 rate 3-year Oral menatetrenone (45 mg/d) during the follow-up period 2-year Hotta et al.18 rate 2-year Oral acyclic retinoid (600 mg) daily for 12 months 3-year Muto et al.19 6-year Transarterial chemotherapy with or without embolization (via catheterized hepatic artery) Gelatin sponge þ Lipiodol (2e3 ml/m2) þ doxorubicin (20 mg/m2) 3-year Izumi et al.20 3-year þ mitomycin C (10 mg/m2), 1 course 3-year Lipiodol (4e10 ml) þ doxorubicin (40 mg/m2) þ mitomycin C Li et al.21 (6 mg/m2), 1e3 courses 3-year Lipiodol (10e20 ml) þ 5-fluorouracil (500 mg/m2) þ adriamycin Peng et al.22 (30 mg/m2) þ gelatin sponge, 2e5 courses Cisplatin (50e80 mg) þ mitomycin C (10 mg), 2e3 courses 3-year Ueno et al.23 Systemic chemotherapy (oral) Oral uraciletegafur (300 mg/d) for 1 year 5-year Hasegawa et al24 5-year 5-year Yamamoto et al.25 Oral carmofur (200 mg) twice daily for as long as possible 5-year Two weeks of capecitabine (1000 mg/m2) twice a day, followed 5-year Xia et al.26 by 1 week of rest, 4e6 cycles 5-year Combination of systemic and transarterial chemotherapy Eight doses of intravenous epirubicin (40 mg/m2) administered 3-year Lai et al.27 at 6-week intervals. In addition, 3 courses of transarterial Lipiodol 3-year (10 ml) and cisplatin (10 mg) Intra-arterial lipiodol-iodine-131 Single dose of 1850 MBq intra-arterial Lipiodol-iodine-131 3-year Lau et al.28 3-year

(continued on next page)

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Table 2 (continued ) Study Immunotherapy Dong et al.29

Weng et al.30 Takayama et al.31 Kuang et al.32

Drugs and dose

Outcomes

Treatment arm (%)

Control arm (%)

p-value

Group I: 41 patients received 3 courses of CIK (1.0  1010e2.0  1010); Group II: 43 patients received 6 courses of CIK (1.0  1010e2.0  1010) Eight infusions of CIK (1.0  1010e1.5  1010)

5-year DFS

11.2

<0.05

36.9

>0.05

recurrence

23.3 (group I) and 19.4 (group II) 37.9 (group I) and 38.1 (group II) 8.9

30

<0.05

DFS OS DFS OS

38 68 75 90

22 62 30 50

<0.05 >0.05 <0.05 <0.05

5-year OS 1-year rate 5-year 5-year 2-year 2-year

Five infusions of lymphocytes (IL-2 þ anti-CD3) (7.1  1010) Three intradermal vaccinations at 2-week intervals

Heparanase inhibitor PI-88 (subcutaneous injection) 57 patients received 160 mg/d PI-88 and another 57 received Liu et al.33 250 mg/d PI-88 over 9 treatment cycles of 4 weeks each. Each treatment cycle consisted of 4 consecutive days per week.

48-week DFS Time to recurrence

63 (160 mg/d), 41 50 >0.05 (250 mg/d) HR ¼ 0.61, P ¼ 0.13 (160 mg/d), P > 0.05 (250 mg/d)

Abbreviations: CIK, cytokine-induced killer cells; DFS, disease-free survival; MIU, NR, not reported; OS, overall survival. a Patients with stage I disease.

leukocytopenia, and thrombocytopenia. Rarely noted adverse effects were elevated alanine aminotransferase, alopecia, depression, and hyperthyroidism. IFN therapy was discontinued in 50 (11%) of 461 patients as a result of adverse events of varying severity, such as thrombocytopenia, depression or loss of appetite, fatigue, renal abscess, arthralgia, hyperthyroidism, neutropenia, lymphopenia, convulsions, and hepatotoxicity. Most patients receiving continuous IFN therapy experienced thrombocytopenia and neutropenia of sufficient severity that the IFN dose had to be reduced. Life-threatening adverse events were not observed. Vitamin analog No problematic adverse effects or abnormal laboratory data were observed as a result of VK2 analog treatment. Only one patient given acyclic retinoid reported a severe headache on the first day of therapy.19 Chemotherapy and intra-arterial lipiodol-iodine-131 therapy There were no treatment-related deaths. The most severe adverse event was extensive hepatic failure in one patient, which may be attributable to TACE therapy.20 Other mild, transient and tolerable adverse effects due to TACE therapy included fever, nausea, ascites, fatigue and leukopenia. In the study by Yamamoto et al.,25 oral carmofur therapy was suspended due to adverse effects in 12 (44%) of 38 patients, mostly because of neuropathy (18.5%) or liver dysfunction (18.5%). However, Hasegawa et al.24 reported negligible toxicity of uraciletegafur on liver function. Nausea (7 of 30 patients) and diarrhea (5 of 30) were the most common adverse effects of oral capecitabine. Two patients withdrew from capecitabine therapy because of repeated grade III nausea or low white blood cell and platelet counts. In the study by Lai et al.,27 three (13%) of 24 patients who underwent

transarterial chemotherapy via a subcutaneous port suffered severe epigastric pain or local cellulitis due to extravasation around the port. No severe adverse effects attributable to lipiodol-iodine-131 were reported. Immunotherapy Fever (61%) was the main adverse effect of AIT and tumor vaccine therapy. Due to persistent fever (<38.5  C), 5 (6%) of 84 patients failed to complete CIK immunotherapy.29 Other rare adverse effects included headache, nausea, dizziness, itching, tachycardia, erythema, dry desquamation and pruritus at the vaccinated sites. All adverse events were grade 1 or 2 and self-limiting. No patient showed any sign of hepatic or renal functional deterioration, pulmonary symptoms or autoimmune disorders. No treatment-related deaths were reported. Heparanase inhibitor PI-88 Overall, 109 (95.6%) of 114 patients in the treatment group had 819 adverse events. However, over 80% of the reported events were “mild” or “moderate”. Over 60% of the reported adverse events were “unrelated” or “unlikely related” to the PI-88 treatment regimen. Less than 2% adverse events were definitely related to the regimen. Of these events, patients receiving a high dose of PI-88 reported higher incidence of treatment-related neutropenia, thrombocytopenia, injection site hemorrhage, prothrombin time prolongation, muscle spasm, and alopecia than patients in the low-dose group. Discussion The current study systematically reviewed the published RCTs of postoperative therapies for patients with HCC after curative treatments and sought to evaluate their efficacy using meta-analysis or a descriptive approach. The cumulative

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evidence indicates that adjuvant IFN reduces the 2-year recurrence rate and improves the 2-year OS, and that chemopreventive VK2 analog therapy improves 1-year OS. Systemic and loco-regional chemotherapy as well as chemotherapy combined with embolization were not as effective as expected. Adjuvant AIT and heparanase inhibitor PI-88 may delay tumor recurrence. Postoperative therapies with acyclic retinoid, intra-arterial lipiodol-iodine-131, or tumor vaccination showed positive results, but more studies are needed (Table 2). No treatment-related deaths were reported. The treatment with chemopreventive vitamin analog was the safest therapy. Conversely, IFN had frequent adverse effects that may not be tolerated by some patients. There are two patterns of HCC recurrence.36 Early-phase (<2 years) and late-phase (>2 years) tumor recurrence differ in their biological patterns and clinical courses, and as a result they have different prognoses. Early-phase recurrence in the remnant liver can originate from intrahepatic metastasis of the primary tumor, while late-phase recurrence can originate from multicentric occurrence in the remnant liver.37 The conventional indicators of poor prognosis in early-phase recurrence are vascular invasion,38,39 tumor multiplicity40 and large tumor size39; whereas risk factors of liver carcinogenesis are associated with late-phase recurrence.41 Hepatitis activity in the preoperative period may contribute to earlyphase42 or late-phase recurrence.43 In fact, most cases of HCC are attributable to hepatitis virus infection and chronic heavy alcohol consumption, which leads to cirrhosis of the liver. Thus, most HCC patients are infected with the hepatitis virus and have cirrhosis. Individual patients may possess different indicators of poor prognosis related to early- and latephase recurrence. As a result, postoperative therapy for each patient should be determined based on his or her indicator(s) of poor prognosis. Given that one patient may present multiple indicators of poor prognosis, combination therapy may be necessary. Ideally postoperative therapy should not only treat micro-metastases from the original tumor (early-phase recurrence), but also prevent new, secondary tumors from developing in the remnant liver (late-phase recurrence). IFN works by several therapeutic mechanisms to exert antiviral, immunomodulatory, antiproliferative and antiangiogenic effects. Its antiviral effect may delay cirrhosis progression and liver function deterioration, thereby improving longterm OS. Its immunomodulatory and antiangiogenic effects may prevent secondary tumor formation in the remnant liver. Its antiproliferative effect may inhibit growth of micro-metastases of the original tumor. Retrospective analysis showed that adjuvant IFN therapy prevented early recurrence in patients with HCC.44 Three RCTs9,11,13 concluded that IFN significantly improved 5-year OS, but three other RCTs6e8 reported no effect on OS. The cumulative evidence shows that adjuvant IFN significantly reduces the 2-year recurrence rate and improves the 2-year OS. Therefore, this therapy has clear benefits for patients with HCC after curative treatments.

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VK2 analog may inhibit the expression of hepatomaderived growth factor45 and exerts strong antiangiogenic effects. The rationale for chemoprevention using VK2 analog is to prevent the development of secondary tumors in the remnant liver. However, the cumulative evidence indicates that VK2 analog does not reduce the 1-year recurrence rate, although it does improve the 1-year OS. The therapy seems safe in the short term: only 2 of 468 treated patients and 9 of 289 control patients died in the first observation year. Since the follow-up of these five RCTs was not long enough, the long-term effect of VK2 analog on OS remains unknown. Acyclic retinoid may inhibit development of secondary HCC and improve OS by deleting malignant clones.34 This may explain why, after a median follow-up of 62 months, the studies reported that acyclic retinoid has a greater effect on the OS in the long term than in the short term.34,35 The objective of adjuvant regional therapies targeting the remnant liver, such as TACE, TAC and intra-arterial lipiodol-iodine-131, is to eradicate preexisting microscopic tumor foci that imaging modalities fail to detect before hepatic resection. However, adjuvant therapies cannot prevent development of secondary HCC in cirrhotic liver in the long term.46 Nevertheless, adjuvant TACE was shown to be beneficial for HCC patients with high risk factors of recurrence.47 It may be that lipiodol-iodine-131 has a similar effect, but the study by Lau et al.28 ended prematurely, leaving this question open. Like adjuvant therapies, conventional systemic chemotherapy inhibits tumor proliferation but cannot prevent a new tumor from forming. Nevertheless, HCC patients with stage I disease may profit from adjuvant oral carmofur therapy.25 In AIT, effector cells may remove residual tumor cells48 and AIT may efficiently improve the immunological status of patients with HCC. Their progress, however, may depend on the underlying liver function. In addition, AIT cannot prevent multicentric relapse. This may explain why AIT decreases only the rate of recurrence but not improves OS. Research has suggested that some additional drugs show promise as postoperative HCC therapies. Some doubleblind, multicenter, Phase III RCTs indicate that sorafenib is effective for the treatment of advanced HCC.49,50 Sorafenib may be an appropriate option for the treatment of HCC after curative resection or ablation. A Phase III trial is underway to evaluate the safety and efficacy of sorafenib compared to placebo in the adjuvant treatment of HCC. Another therapy that shows promise is thalidomide, which some researchers have reported to improve 2-year DFS.51 Hopefully, the coming years will bring a clearer picture of the efficacy and safety of the various postoperative therapy options available. Limitations This systematic review included only patients with HCC treated by curative resection or local ablation, and it included studies involving no adjuvant or chemopreventive treatment arm. Second, four of the included studies were

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of low methodological quality. Third, some studies failed to report the proportion of patients lost to follow-up or reported proportions greater than 15%, which can lead to incomplete outcome bias.52 Fourth, the proportion of patients who adhered to the protocol completely was very low in some studies. Fifth, intention-to-treat analysis was performed in only 15 (53.6%) of 28 studies. The true potential efficacy of the therapy may overstate when intention-totreat was not performed. Lastly, sample size was too small in many of the studies. Only 10 studies reported statistical calculations to determine optimal sample size, and 4 studies involved 30 patients or less. Such small sample sizes may mask clinically significant effects and may compromise the ability of randomization to protect against bias from unmeasured confounders.53 Conclusion The present analysis demonstrates that adjuvant acyclic retinoid, lipiodol-iodine-131 and tumor vaccination may improve the OS of patients with HCC after curative treatments. The effect of IFN on OS is the most definite. On the other hand, IFN therapy is frequently associated with adverse effects. Since acyclic retinoid enhances the sensitivity of HCC cells to IFN,54 further work is needed to investigate combinations of postoperative therapies, such as IFN with acyclic retinoid.

Acknowledgments The authors thank Dr Armando Chapin Rodrıguez and Dr Liu-Cheng Wu for their language editing, which substantially improved the quality of the manuscript. This work was supported by a grant from the National Natural Science Foundation of China (Project No. 81160262/ H1602 to L-Q L), which did not play any role in the design of the study, in the collection or analysis of data, or in the writing of the manuscript. Appendix. Supplementary material Supplementary data related to this article can be found online at doi:10.1016/j.ejso.2012.01.006. Disclosure None. Funding This work was supported by a grant from the National Natural Science Foundation of China (Project No: 81160262/H1602) to Le-Qun Li.

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