Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis

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http://dx.doi.org/10.1016/j.hpb.2017.04.016

REVIEW ARTICLE

Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis Jack P. Silva1, Nicholas G. Berger1, Susan Tsai1, Kathleen K. Christians1, Callisia N. Clarke1, Harveshp Mogal1, Sarah White2, William Rilling2 & T. Clark Gamblin1 1

Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA, and 2Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA

Abstract Background: Transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) remains controversial. This systematic review sought to examine the role of TACE in the treatment of HCC with PVT in either the main portal vein (MPV) or portal vein branches (PVB). Methods: PubMed was searched for “hepatocellular carcinoma” and “transarterial chemoembolization” from January 1, 2006 to August 31, 2016. Cohorts treated with TACE for HCC with PVT were included. Meta-analysis of overall survival (OS), mRECIST response, and complication incidence was performed. MPV and PVB subgroups were compared. Results: Of 136 search results, 13 studies with 1933 TACE patients were included. Median OS (95% CI) was eight (5–15) months. Survival rates after one, three, and five years were 29% (20%–40%), 4% (1%–11%), and 1% (0%–5%), respectively. Only 1% experienced liver failure and 18% had posttreatment complications. Patients with MPV thrombosis had worse survival than PVB patients (p < 0.001), but similar mRECIST response rates (14% vs. 16%, p = 0.238). Conclusion: TACE is a safe treatment for a highly selected population of HCC patients with PVT. Despite worse survival rates compared to PVB thrombosis, PVT in the MPV should not be considered an absolute contraindication to TACE. Received 3 March 2017; accepted 29 April 2017 Presented at the Twelfth International Symposium on Regional Cancer Therapies, Snowbird, UT, USA, February 2017.

Correspondence T. Clark Gamblin, Department of Surgery, Division of Surgical Oncology, Medical College of Wisconsin, 9200 West Wisconsin Ave, Milwaukee, WI 53226, USA. E-mail: [email protected]

Introduction Despite advancements in early diagnosis and screening for hepatocellular carcinoma (HCC), many patients still present with advanced disease beyond the indications for curative interventions like resection, ablation, or transplant. Management for these patients is focused on liver-directed palliative treatments or supportive care. Two randomized controlled trials published in 2002 showed transarterial chemoembolization (TACE) to be superior to This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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supportive care in highly selected patients with unresectable HCC.1,2 However, many patients were excluded from these trials due to the presence of portal vein thrombosis (PVT). Patients with HCC and PVT have a very poor prognosis, with an expected survival of 2–4 months with the best supportive care.3 The Barcelona Clinic Liver Cancer (BCLC) staging system for HCC is one of the most broadly acknowledged worldwide. In these management guidelines, HCC with PVT is advanced stage (C) disease, and systemic therapy with Sorafenib is the recommended treatment.4 However, survival following Sorafenib administration in these patients is limited, with only a modest improvement over placebo.5 Despite the BCLC recommendations, a recent survey of

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Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016

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interventional oncologists demonstrated that TACE is chosen by 52% of physicians when treating HCC with PVT.6 The ideal treatment strategy for patients with advanced HCC, such as those with PVT, remains undefined and the selection criteria for TACE is evolving. PVT has been described as a relative contraindication to TACE due to the potential for embolization to cause hepatic infarction and worsened liver function. Patients with tumors obstructing the main portal vein are theoretically at a higher risk for this complication, and many prior series have excluded such patients. However, several studies since the landmark trials in 2002 have reported a potential benefit in treating some HCC patients with PVT in the main portal vein.7 The aim of the current systematic review and meta-analysis was to describe survival, complication rates, and treatment response following TACE for HCC patients with PVT. Outcomes were also compared between subgroups of patients with PVT obstruction in the main portal vein (MPV) or portal vein branches (PVB).

Methods Study selection Studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement (Fig. 1).8 PubMed was queried using the terms “hepatocellular

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-

Analysis (PRISMA) flowchart for the current review and meta-analysis of outcomes following treatment with transarterial chemoembolization (TACE) for hepatocellular carcinoma with portal vein thrombosis (PVT).

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carcinoma” and “transarterial chemoembolization” for publications from 2006 through August 2016. This time period was defined to reflect contemporary studies using modern TACE techniques. Results of the PubMed search only included clinical studies with full text available in English. Such studies were then reviewed in detail to select studies reporting outcomes for patients with portal vein thrombosis. Studies fit for inclusion were comprised of randomized prospective trials and retrospective studies comparing TACE to another treatment for management of HCC with PVT. All studies with a “TACE only” treatment arm were considered for selection irrespective of the comparison arm intervention, provided the TACE cohort received no other treatments that could have affected outcomes. All patients examined in the meta-analysis had PVT and were treated with TACE. Specific reasons for study exclusion were: 1) no report of PVT, 2) lack of dedicated TACE treatment arm, 3) limitation of PVT extent, 4) less than 30 patients receiving TACE in the study, or 5) non-selective chemoembolization technique. A critical appraisal of the studies was completed using the Newcastle– Ottawa Scale (Supplemental Table 1). PVT classification Three methods of PVT classification were utilized for subgroup analysis (Supplemental Table 2). The extent of PVT obstruction was simplified into MPV thrombus or PVB thrombus. MPV invasion included Kaplan–Meier Type A, Cheng Types III-IV, and Japanese Vp4. All others were defined as PVB invasion. Data analysis The primary outcome of interest for patients undergoing TACE for HCC with PVT was median survival time. Secondary measures analyzed were 1-, 3-, and 5-year survival rates, treatment response rate, treatment complications, liver failure, and number of treatments. Treatment response was classified using the modified RECIST criteria (mRECIST), which grades the tumor response as complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD).9 For metaanalysis, a positive response was defined as CR or PR within two months of treatment. Complications following treatment were defined individually by each of the included studies, but post-embolization syndrome was not included as a complication. Similarly, criteria for liver failure was defined separately by each study. Survival and response rates were extracted from each study individually before being entered into random-effects models to determine the pooled estimates. The analyses were weighted according to sample size for each model. The models were represented graphically as Forest plots for survival rates and response rates for each study. Pearson chi-squared tests were used to assess study heterogeneity. Median survival times were extracted individually from each study and a pooled estimate was determined using weighted means according to sample size. The process described above was repeated for cohorts with MPV occlusion, and again for cohorts with PVB occlusion. Outcomes

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Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016

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Figure 2 Forest plots demonstrating pooled estimates of one-year survival following treatment with transarterial chemoembolization for he-

patocellular carcinoma with portal vein thrombosis for a) all patients, b) patients with main portal vein (MPV) invasion, and c) patients with portal vein branch (PVB) invasion.

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© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016

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Figure 3 Forest plots demonstrating pooled estimates of response rates following treatment with transarterial chemoembolization for hepa-

tocellular carcinoma with portal vein thrombosis for a) all patients, b) patients with main portal vein (MPV) invasion, and c) patients with portal vein branch (PVB) invasion.

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© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016

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Table 1 Results from each study in the meta-analysis reporting outcomes for patients receiving transarterial chemoembolization (TACE) for

hepatocellular carcinoma with portal vein thrombosis (PVT). Results are subclassified into main portal vein (MPV) and portal vein branch (PVB) groups. Response rate is defined by complete or partial response according to the mRECIST criteria. Complications do not include post-embolization syndrome Author

n

Median survival time (months)

3-year survival (%)

5-year survival (%)

All PVT

All PVT

All PVT

MPV

PVB

MPV

PVB

MPV

PVB

Liver failure (%)

Complications (%)

Lu

33

9

–

–

–

–

–

–

–

–

0

–

Luo11

84

7

5

10

–

0

–

–

0

–

0

–

Niu12

115

9

7

13

–

–

–

–

–

–

–

–

Peng13

402

13

–

–

7

4

7

1

0

1

7

–

Wang14

604

5

4

6

6

5

7

4

4

5

–

–

Yang15

42

5

5

–

0

0

–

0

0

–

0

0

Ye16

86

7

–

–

0

–

–

0

–

–

–

–

10

17

Zhu

45

6

3

8

0

0

0

0

0

0

0

49

Kasai18

60

–

–

–

–

–

–

–

–

–

0

0

Chung19

83

6

6

–

1

1

–

0

0

–

0

29 6

49

15

–

–

–

–

–

–

–

–

0

Kim KM21

149

8

5

9

–

–

–

–

–

–

–

–

Liu22

181

–

–

32

43

–

43

33

–

33

–

–

8

5

11

4

2

10

1

0

6

1

18

Kim JH

20

Pooled estimates

for MPV vs. PVB groups were compared using a two-tailed t-test. Liver failure and treatment complications were tallied individually from each study, summed, and represented as proportions of events over total number of patients at risk. Studies reported complications defined by the National Cancer Institute Common Terminology Criteria for Adverse Events. The median number of TACE procedures was extracted individually from each study and a pooled estimate was determined using weighted means according to sample size.

Results Studies included in meta-analysis All studies were from Asian countries, with eight from China,10–17 one from Japan,18 three from Korea,19–21 and one from Taiwan.22 Publication dates were all between 2009 and 2016. All studies included outcomes of interest for a cohort of HCC patients who had PVT, resulting in 1933 patients treated with TACE alone included in the meta-analysis (Fig. 1). Ten studies10–17,19,21 provided patients classified as having MPV

Table 2 Pooled estimates for survival and response rates for patients receiving transarterial chemoembolization for hepatocellular carci-

noma with portal vein thrombosis in the main portal vein (MPV) or in a portal vein branch (PVB) Rate

95% CI

Range

Study Heterogeneity (I2)

p-value

MPV

0.16

0.07–0.28

0.00–0.37

91.0%. p < 0.001

<0.001

PVB

0.37

0.23–0.51

0.06–0.60

92.5%, p < 0.001

MPV

0.02

0.00–0.04

0.00–0.05

42.1%, p = 0.120

PVB

0.10

0.01–0.27

0.00–0.43

96.0%, p < 0.001

MPV

0.00

0.00–0.02

0.00–0.04

64.0%, p = 0.020

PVB

0.06

0.00–0.20

0.00–0.33

95.7%, p < 0.001

MPV

0.14

0.09–0.20

0.00–0.19

17.8%, p = 0.300

PVB

0.16

0.08–0.26

0.06–0.20

60.9%, p = 0.080

One-year survival

Three-year survival <0.001

Five-year survival <0.001

mRECIST response

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0.238

© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016

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occlusion available for analysis (n = 806), and ten studies10– 14,16–18,21,22 provided PVB patients available for analysis (n = 995). Patient selection consensus Selection criteria for patients eligible to receive TACE varied between studies (Supplemental Table 3), but TACE was typically only offered to Child-Pugh class A or B patients.10–17,19 Several studies also excluded patients with distant metastasis12,14,16,18,22 or PVT in the main portal vein.18,22 TACE technique Details of the TACE procedure were similar for all studies. A ‘selective’ or ‘super-selective’ technique was universally applied. In general, a microcatheter was advanced into the hepatic arterial circulation to the most distal tumor-feeding vessel to treat the maximum tumor perfusion, while sparing the non-tumor hepatic parenchyma. Most commonly, an emulsion of lipiodol and one or more chemotherapeutic agents was administered. Occlusion of the feeding vessels was achieved by injecting gelatin sponge particles or other embolic materials if deemed necessary. Stasis was often confirmed by monitoring the flow of contrast material. Outcomes following TACE for HCC with PVT The one-year survival rate reached nearly 30% for all patients selected to receive TACE (Fig. 2a), and the mRECIST response rate was nearly 20% (Fig. 3a). The median survival time and survival rates at three and five years are shown in Table 1. The weighted estimate of median number of TACE procedures performed per patient was 2 (range 2–4). Incidences of liver failure and post-treatment complications are reported in Table 1. MPV vs. PVB thrombus Results of the random effects model used to determine pooled survival and response rates for patients with MPV and PVB thrombosis are displayed as Forest plots in Figs. 2b,c and 3b,c. Survival rates for patients with MPV occlusion were significantly worse than those with PVB occlusion at one, three, and five years, but mRECIST response rates were similar (Table 2). The weighted estimate of median (range) survival time for all patients receiving TACE for HCC with MPV occlusion was 5 (3–7) months, which was significantly shorter than the 11 (6–32) months for patients with PVB occlusion (p < 0.001).

Discussion The pooled estimates from the current study show that TACE can be safely administered in well-selected patients with HCC and PVT, despite concerns about functional liver reserve. Liver failure in the follow-up period was exceedingly rare in this population that largely excluded Child-Pugh class C patients. Treatment and control arms varied among studies in the meta-

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analysis, but those comparing TACE to conservative treatment demonstrated a clear survival advantage for TACE regardless of PVT extent. Yet still, prognosis for patients with PVT remains poor, regardless of treatment. Direct comparison between outcomes for patients with MPV vs. PVB occlusion undergoing TACE revealed significantly lower survival in patients with MPV thrombosis, but treatment response rates were similar. Despite increased treatment options and technological advancements, survival following treatment for HCC with PVT has not changed significantly. The current meta-analysis revealed a mean overall survival of eight months and one-year survival rate of 29%. Results are similar to a single institutional report of TACE for treatment of HCC with PVT between 2000 and 2004, which reported a median overall survival of 10 months, and a one-year survival rate of 25%.23 Descriptions of such cohorts with PVT treated by TACE are unusual prior to 2002. The two randomized trials published that year describing the benefit of TACE in unresectable HCC did not focus on PVT. In fact, Lo et al. excluded patients with MPV thrombosis, and Llovet et al. excluded all patients with PVT, even in segmental branches.1,2 Improvements in TACE technique have allowed a broader selection criteria for treatment of HCC patients. TACE is now a treatment option for patients who previously would only be candidates for supportive care due to the extent of their disease at diagnosis. The survival advantage of TACE compared to supportive care is well-described by four of the studies included in the current meta-analysis. In a prospective controlled study of 150 patients from 2007 to 2010, Niu et al. demonstrated that TACE was superior to conservative treatment for HCC with PVT, with a significantly longer median overall survival in the TACE cohort (9 vs. 1 months, p < 0.001).12 Ye et al. described a group of 338 HCC patients treated for PVT between 2007 and 2009, which showed improved median overall (7 vs. 4 months) and one-year survival (18% vs. 0%) for TACE patients compared to those given conservative management.16 A prospective nonrandomized study performed by Luo et al. from 2007 to 2009 also demonstrated the advantage of TACE over conservative treatment for HCC in 164 patients with PVT. TACE patients had significantly longer median overall survival (7 vs. 4 months, p < 0.001) and a better one-year survival rate (31% vs. 4%).11 Chung et al. compared TACE to supportive care for treatment of HCC with MPV thrombosis in a retrospective study of 125 patients between 2003 and 2007, and multivariate analysis showed treatment with TACE to be an independent predictor of improved survival (HR 0.263; 95% CI 0.164–0.424).19 A meta-analysis from Xue et al., in 2013 further supported the advantage of TACE compared to supportive management. They reported on 923 patients from eight controlled trials with a combined survival hazard ratio of 0.44 (95% CI 0.34–0.57) for TACE compared to conservative treatment at one year.7 The current meta-analysis further describes the expected outcomes following TACE for HCC patients with PVT by combining 13 contemporary studies to examine a

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Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016

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larger patient population with a longer follow-up time relative to the study from Xue and colleagues. The ability to administer TACE for patients with HCC and PVT can be attributed to superselective catheterization. Arterial embolization of the liver was originally conceptualized to control both detected and potential malignancies, thus TACE was historically employed for lobar or even whole-liver treatments. Such a method would carry significant risk for patients with PVT, due to diminished portal perfusion. More recent advancements have led to microcatheters that now measure 1.7–2.4 French, often allowing for advancement into the most distal tumor-feeding subsegmental hepatic arteries. These “superselective” or “ultraselective” techniques utilized in the included studies are the current standard, and have allowed HCC patients with PVT to be considered for TACE. Even with a MPV occlusion, superselective TACE can preserve some arterial perfusion to minimize the risk of the ischemic necrosis of normal parenchyma and subsequent liver failure. This theoretically safe application of therapy is supported by the current meta-analysis, where less than 1% of patients suffered from liver failure after treatment, and mRECIST response rates were similar for both PVB and MPV patients. Sorafenib is the only treatment endorsed by BCLC recommendations for Advanced Stage (C) HCC. However, these guidelines may not reflect the current practice. Superiority of TACE compared to Sorafenib is not well-established, but the addition of TACE has been proven safe and effective.17,24–27 The GIDEON registry collects worldwide data for patient characteristics, treatment patterns, and outcomes for HCC patients receiving Sorafenib for HCC.28,29 Studies stemming from the registry may provide further clarification of the differences in outcomes for TACE and Sorafenib. TACE alone is not the only treatment for HCC with PVT that has made progress in recent years. A variety of new locoregional therapies and proposed combination treatments have also been investigated. Current National Comprehensive Cancer Network (NCCN) guidelines provide a variety of treatment options for unresectable HCC, listed without regard to treatment preference.30 In addition to TACE, the NCCN offers ablation, external beam radiation, Sorafenib, or clinical trials as treatment options. The current decision to utilize TACE for HCC patients with PVT should rely on patient performance status, extent of PVT, and baseline liver function. This study is subject to several limitations. As with all metaanalyses, some degree of heterogeneity between the studies is expected. Differences between the patient populations examined may stem from severity of disease, physician or hospital diversity, or any number of other patient- or disease-related variables. Heterogeneity was described for each of the outcome analyses performed, and some improvement was seen after dividing patients according to PVT extent (Table 2). Several of the studies were non-randomized or retrospective, allowing for patient selection bias to influence the results. For example, patients with HPB 2017, -, 1–8

improved liver function are more likely to be offered TACE, and may have a higher chance of survival compared to a patient with poor liver function who was offered conservative management in retrospective series. However, only two of the studies included did not receive the highest possible 9/9 rating using the Newcastle– Ottawa Scale (Supplemental Table 1). Each of the studies included represented patients in an Asian country. Regional differences in HCC etiologies and treatments exist, so the current meta-analysis may not be generalizable to Western populations. In conclusion, TACE is a safe treatment for HCC with PVT in select Child-Pugh class A and B patients; studies reporting such treatment methods demonstrate an acceptable complication incidence. Prognosis remains relatively poor in patients treated with TACE, but a historically stable survival advantage persists compared to supportive care. Given the demonstrable safety and similar treatment response rates for MPV and PVB patients, PVT should not be considered an absolute contraindication to TACE, regardless of thrombus extent. The use of TACE in this highly selected population of HCC patients with PVT is justified despite the lack of support in some treatment guidelines.

Conflict of interest None to declare. References 1. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J et al. (2002) Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359:1734–1739. 2. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT et al. (2002) Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology (Baltimore, Md) 35:1164–1171. 3. Han K, Kim JH, Ko GY, Gwon DI, Sung KB. (2016) Treatment of hepatocellular carcinoma with portal venous tumor thrombosis: a comprehensive review. World J Gastroenterol 22:407–416. 4. Llovet JM, Bru C, Bruix J. (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19:329–338. 5. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF et al. (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390. 6. Gaba RC. (2012) Chemoembolization practice patterns and technical methods among interventional radiologists: results of an online survey. Am J Roentgenol 198:692–699. 7. Xue TC, Xie XY, Zhang L, Yin X, Zhang BH, Ren ZG. (2013) Transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a meta-analysis. BMC Gastroenterol 13:60. 8. Moher D, Liberati A, Tetzlaff J, Altman DG. (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012. 9. Lencioni R, Llovet JM. (2010) Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 30:52–60. 10. Lu DH, Fei ZL, Zhou JP, Hu ZT, Hao WS. (2015) A comparison between three-dimensional conformal radiotherapy combined with interventional

© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016

HPB

8

treatment and interventional treatment alone for hepatocellular carci-

21. Kim KM, Kim JH, Park IS, Ko GY, Yoon HK, Sung KB et al. (2009)

noma with portal vein tumour thrombosis. J Med Imaging Radiat Oncol

Reappraisal of repeated transarterial chemoembolization in the treat-

59:109–114.

ment

11. Luo J, Guo RP, Lai EC, Zhang YJ, Lau WY, Chen MS et al. (2011)

of

hepatocellular

carcinoma

with

portal

vein

invasion.

J Gastroenterol Hepatol 24:806–814.

Transarterial chemoembolization for unresectable hepatocellular carci-

22. Liu PH, Lee YH, Hsia CY, Hsu CY, Huang YH, Chiou YY et al. (2014)

noma with portal vein tumor thrombosis: a prospective comparative

Surgical resection versus transarterial chemoembolization for hepato-

study. Ann Surg Oncol 18:413–420.

cellular carcinoma with portal vein tumor thrombosis: a propensity

12. Niu ZJ, Ma YL, Kang P, Ou SQ, Meng ZB, Li ZK et al. (2012) Transarterial chemoembolization compared with conservative treatment for advanced

score analysis. Ann Surg Oncol 21:1825–1833. 23. Georgiades CS, Hong K, D’Angelo M, Geschwind JF. (2005) Safety and

hepatocellular carcinoma with portal vein tumor thrombus: using a new

efficacy of transarterial chemoembolization in patients with unresect-

classification. Med Oncol (Northwood, London, England) 29:2992–2997.

able hepatocellular carcinoma and portal vein thrombosis. J Vasc Interv

13. Peng ZW, Guo RP, Zhang YJ, Lin XJ, Chen MS, Lau WY. (2012) Hepatic

Radiol 16:1653–1659.

resection versus transcatheter arterial chemoembolization for the

24. Chung YH, Han G, Yoon JH, Yang J, Wang J, Shao GL et al. (2013)

treatment of hepatocellular carcinoma with portal vein tumor thrombus.

Interim analysis of START: study in Asia of the combination of TACE

Cancer 118:4725–4736.

(transcatheter arterial chemoembolization) with sorafenib in patients

14. Wang K, Guo WX, Chen MS, Mao YL, Sun BC, Shi J et al. (2016)

with hepatocellular carcinoma trial. Int J Cancer 132:2448–2458.

Multimodality treatment for hepatocellular carcinoma with portal vein

25. Erhardt A, Kolligs F, Dollinger M, Schott E, Wege H, Bitzer M et al.

tumor thrombus: a large-scale, multicenter, propensity matching score

(2014) TACE plus sorafenib for the treatment of hepatocellular carci-

analysis. Medicine 95:e3015.

noma: results of the multicenter, phase II SOCRATES trial. Cancer

15. Yang M, Fang Z, Yan Z, Luo J, Liu L, Zhang W et al. (2014) Transarterial

Chemother Pharmacol 74:947–954.

chemoembolisation (TACE) combined with endovascular implantation

26. Pan T, Li XS, Xie QK, Wang JP, Li W, Wu PH et al. (2014) Safety and

of an iodine-125 seed strand for the treatment of hepatocellular carci-

efficacy of transarterial chemoembolization plus sorafenib for hepato-

noma with portal vein tumour thrombosis versus TACE alone: a two-

cellular carcinoma with portal venous tumour thrombus. Clin Radiol 69:

arm, randomised clinical trial. J Cancer Res Clin Oncol 140:211–219.

e553–61.

16. Ye JZ, Zhang YQ, Ye HH, Bai T, Ma L, Xiang BD et al. (2014) Appropriate

27. Zheng J, Shao G, Luo J. (2014) Analysis of survival factors in patients

treatment strategies improve survival of hepatocellular carcinoma pa-

with intermediate-advanced hepatocellular carcinoma treated with

tients with portal vein tumor thrombus. World J Gastroenterol 20:

transcatheter arterial chemoembolization combined with sorafenib. Clin

17141–17147.

Transl Oncol Off Publ Fed Span Oncol Soc Natl Cancer Inst Mexico 16:

17. Zhu K, Chen J, Lai L, Meng X, Zhou B, Huang W et al. (2014) Hepa-

1012–1017.

tocellular carcinoma with portal vein tumor thrombus: treatment with

28. Geschwind JF, Kudo M, Marrero JA, Venook AP, Chen XP,

transarterial chemoembolization combined with sorafenib–a retro-

Bronowicki JP et al. (2016) TACE treatment in patients with sorafenib-

spective controlled study. Radiology 272:284–293.

treated unresectable hepatocellular carcinoma in clinical practice: final

18. Kasai K, Ushio A, Kasai Y, Sawara K, Miyamoto Y, Oikawa K et al.

analysis of GIDEON. Radiology 279:630–640.

(2013) Therapeutic efficacy of transarterial chemo-embolization with a

29. Kudo M, Lencioni R, Marrero JA, Venook AP, Bronowicki JP, Chen XP

fine-powder formulation of cisplatin for hepatocellular carcinoma. World

et al. (2016) Regional differences in sorafenib-treated patients with he-

J Gastroenterol 19:2242–2248.

patocellular carcinoma: GIDEON observational study. Liver Int 36:

19. Chung GE, Lee JH, Kim HY, Hwang SY, Kim JS, Chung JW et al. (2011) Transarterial chemoembolization can be safely performed in patients

1196–1205. 30. Network NCC. (2016) Clinical practice guidelines for hepatobiliary can-

with hepatocellular carcinoma invading the main portal vein and may

cers [Version 2]. Available from: https://www.nccn.org/professionals/

improve the overall survival. Radiology 258:627–634.

physician_gls/pdf/hepatobiliary.pdf.

20. Kim JH, Yoon HK, Kim SY, Kim KM, Ko GY, Gwon DI et al. (2009) Transcatheter arterial chemoembolization vs. chemoinfusion for unre-

Appendix A. Supplementary data

sectable hepatocellular carcinoma in patients with major portal vein

Supplementary data related to this article can be found at http://dx.doi.org/

thrombosis. Aliment Pharmacol Ther 29:1291–1298.

10.1016/j.hpb.2017.04.016.

HPB 2017, -, 1–8

© 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Silva JP, et al., Transarterial chemoembolization in hepatocellular carcinoma with portal vein tumor thrombosis: a systematic review and meta-analysis, HPB (2017), http://dx.doi.org/10.1016/j.hpb.2017.04.016