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Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis
HPB
https://doi.org/10.1016/j.hpb.2018.03.015
REVIEW ARTICLE
Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis Ze-xin Zhu1, Xiao-xue Wang2, Ke-fei Yuan1, Ji-wei Huang1 & Yong Zeng1 1 2
Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, 610041, China, and Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, 610041, China
Abstract Background: Hepatocellular carcinoma (HCC) is the most common malignancy in liver. Transarterial chemoembolization (TACE) is recommended as an effective treatment in advanced HCC patients. Recent studies showed iodine-125 seed (a low-energy radionuclide) can provide long-term local control and increase survival for HCC patients. The aim of the study was to evaluate the outcome of TACE plus iodine-125 seed in comparison with TACE alone for HCC. Methods: A comprehensive search of studies among PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted with published date from the earliest to January 10th, 2018. No language restrictions were applied, while only prospective randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) were eligible for a full-text review. The primary outcome was overall survival (OS), response rate (the rate of partial atrophy or complete clearance of the tumor lesion) and adverse events (AEs). The odds ratios (ORs) were combined using either fixed-effects model or random-effects model. All statistical analyses were performed using the Stata 12.0 software. Results: 9 studies were included, involving 894 patients. Among them, 473 patients received combined therapy of TACE plus iodine-125 implantation, compared with 421 patients with TACE alone. Patients receiving combined therapy of TACE plus iodine-125 showed significantly improvement in 1-year OS (OR = 4.47, 95% confidence intervals (CI): 2.97–6.73; P < 0.001), 2-year OS (OR = 4.72, 95% CI: 2.63–8.47; P < 0.001). No significant publication bias was observed in any of the measured outcomes. Conclusions: Based on these findings, TACE plus iodine-125 implantation achieves better clinical efficacy compared with TACE alone in the treatment of HCC. Received 4 February 2018; accepted 28 March 2018
Correspondence Yong Zeng; Ke-fei Yuan; Ji-wei Huang, Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China. E-mails: [email protected] (Y. Zeng); [email protected] (K.-f. Yuan); [email protected] (J.-w. Huang)
Introduction Hepatocellular carcinoma (HCC) is the most common malignancy in liver. Its global incidence has been reported to be on the rise and is predicted to exceed a million patients per year by 2025.1 According to the recent statistics, HCC is the 4th most commonly diagnosed cancers among men, and the 4th leading causes of cancer death among both men and women in China.2 Liver transplantation (LT) and hepatic resection are possible
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curative treatments for HCC patients. Although the improvements in surgical technology had made more HCC tumors resectable, <40% of patients are diagnosed at an early stage and suitable for surgical resection.3 Transarterial chemoembolization (TACE) has been demonstrated to be an effective treatment in improving survival for patients with advanced HCC (stage B/C under the Barcelona Clinic Liver Cancer (BCLC) system).3 The TACE protocol has been
© 2018 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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updated several times.4 The optimal combination of TACE with anti-tumor agent and adjuvant treatments are still are still evolving. TACE combined with other treatments, such as radiofrequency ablation or percutaneous ethanol injection, have been shown to improve overall survival as compared to TACE alone.5,6 Traditionally, radiotherapy (RT) plays a limited role in the treatment of HCC.7,8 However, recent studies showed that TACE in combination with radiotherapy was more therapeutically beneficial than TACE alone for treating HCC patients.9,10 Consistently, two meta-analyses also showed more favorable result.11,12 According to Nag S et al.,13 iodine-125 seed (a low-energy radionuclide), can provide long-term local control and increased survival for HCC patients. Meanwhile, another study also revealed that iodine-125 seed implantation can strongly stimulate the anti-tumor immune response in HCC patients.14 Moreover, two recent studies indicated that the combination therapy with iodine-125 seed implantation was superior to monotherapy in the treatment of HCC.15,16 However, no largescale multicenter clinical research has been reported so far. The aim of this review was to provide a rigorous summary by pooling the results of the currently available data on the survival outcomes of HCC patients who underwent TACE plus iodine125 seed implantation or TACE alone.
Materials and methods The process of the meta-analysis was carried out according to the Cochrane Collaboration recommendations.17 The analysis results were reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.18 Search strategy A comprehensive search of the PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted. The combination of free-text words and MeSH terms used were as follows: “((125) or (iodine seed) or (radiotherapy)) AND ((transcatheter arterial chemoembolization) or TACE or TAE) AND ((liver cancer) or (hepatocellular carcinoma) or (HCC))”. The sensitive searching of clinical trials was under Cochrane’s recommendation.19 The search included literature published until January 10th, 2018 with no lower date limit. No language restrictions were applied, but only prospective randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) were eligible for a full-text review. References of all the main review articles on this topic were analyzed manually to identify any relevant citations missed on the initial search. Two independent researchers performed search. Including and excluding criteria Publications complied with the following criteria were accepted: 1) HCC diagnosed by computed tomography (CT), magnetic resonance imaging (MRI) or pathology; 2) prospective HPB 2018, -, 1–8
randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs); 3) published trials that included a treatment group receiving TACE plus iodine-125 seed implantation and a control group receiving TACE alone; and 4) reported survival rate or tumor response rate on at least 1-year follow-up, while the criteria for tumor response must be described clearly. Abstracts, letters, case reports, and studies without control groups were excluded. In treatment centers with multiple publications, the most recent and/or largest publication was included. Data extraction Data extraction was performed using a standardized form, two authors (Zhu Z and Wang X) collected information regarding study characteristics (such as author name, year of publication, study design, sample size, length of follow-up), intervention characteristics (such as with or without iodine-125, drugs of TACE treatments); patients’ characteristics (such as age, gender, ChildPugh Class, with or without tumor thrombosis); and mortality outcomes (that is, number of deaths and patients included for analyses in each treatment group). Tumor response was evaluated by the change in tumor size on abdominal CT and MRI before and after treatment. Tumor response rates would be recorded according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for HCC. Complete response (CR) was defined as complete clearance of the lesion after treatment; partial response (PR) was defined as 30% decrease in the diameters of target lesions; progressive disease (PD) was defined as 20% increase in the summed diameters of target lesions, taking the smallest summed value recorded since treatment as reference; stable disease (SD) was the summed value lies between PD and PR. The response rate was the sum of CR and PR.20 Quality assessment The risk of bias in RCTs was assessed following Cochrane recommendations, considering random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting. Each category was assessed as low, unclear or high risk of bias and summarized in a table with a plus, question mark or minus, respectively.19 The quality of non-RCTs was assessed using the NewcastleOttawa Scale.21 This scale assesses risk of bias in three domains: 1, selection of the study groups (including representativeness of exposed cohort, selection of non exposed, ascertainment of exposure, outcome not present at start); 2, comparability of groups; and 3, ascertainment of exposure and outcome (including assessment of outcome, adequate follow-up length, adequacy of follow-up). A study can be rated 0–9 stars based on these criteria. Studies with scores >7 were considered as having a low risk of bias, scores of 4–6 as having a moderate risk of bias, and scores <4 as having a high risk of bias. Follow-up was adequate if the median or mean follow-up was in excess of 2-year.
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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Statistical analyses The primary outcome was the overall survival (OS) and the response rate (the rate of partial atrophy or complete clearance of the tumor lesion). Pooled ORs with 95%CI were calculated using either the fixed-effects model or random-effects model. For each meta-analysis, the c2 and I2 statistics were first calculated to assess the heterogeneity of the included studies. P < 0.1 and I2 > 50% were considered significant. For P < 0.1 and I2 > 50%, the random-effects model was used. Otherwise, data were assessed using the fixed-effects model. The significance of the pooled ORs was assessed by the Z-test. P < 0.05 was considered statistically significant. Publication bias was evaluated by Egger’s regression, P < 0.05 were considered as significantly publication bias.17 All statistical analyses were performed using the Stata 12.0 (Stata Corporation, College Station, TX, USA).
Results Literature search and description of the studies The results of the search strategy are shown in Fig. 1. We have searched a total of 471 studies. Finally, 9 studies were included for analysis,16,22–29 including 2 randomized controlled trials (RCTs),16,28 and 7 non-RCTs.22–27,29 These studies were published from 2008 to 2017 and all of them investigated the therapy of TACE plus iodine-125 seed implantation. A total of 894 patients were included in these studies. Among them, 473 (52.9%) patients were carried with TACE plus iodine-125 seed implantation therapy, while 421 (47.1%) patients received TACE alone. Individual study data are shown in Supplementary Table 1. Generally, Lipiodol was mixed with the drugs at a uniform
Figure 1 Identification of eligible studies from databases
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dosage or a dosage calculated according to the tumor size before the procedure. The dosage of Lipiodol ranged from 2 to 20 mL. Iodine-125 seed implantation was performed under the guidance of ultrasound or Computed Tomography (CT) with local anesthesia. Patients in the test group underwent iodine-125 seed implantation therapy after TACE. Quality assessment The overall risk of all types of bias in the RCTs was generally low to unclear (Supplementary Fig. 1A and 1B). Non-RCT Studies included were all 6 stars or above by the Newcastle Ottawa scale (Supplementary Table 2). Overall survival rate 1-, 2-year survival rate were compared. The heterogeneity was low among the trials. Seven studies,16,22–25,27,29 reported 1-year survival. TACE plus iodine-125 seed implantation (427 (54.6%) patients) was associated with a higher one-year survival rate compared with TACE alone (355 (45.4%) patients) (odds ratio (OR): 4.47, 95% confidence intervals (CI): 2.97–6.73; P < 0.001). The total survival benefit of iodine-125 seed implantation therapy is significant (Fig. 2). Two-year survival rate was reported in 2 studies,22,24 TACE plus iodine-125 seed implantation (248 (59.0%) patients) has a higher two-year survival rate compared with TACE alone (172 (41.0%) patients) (OR: 4.72, 95% CI: 2.63–8.47; P < 0.001) (Fig. 3). Response rate (CR + PR) 6 studies,16,22,23,25,26,38 compared the response rate, including 590 patients. They all followed the RECIST after treatment. The result of heterogeneity tests among trials was P = 0.267, I2 = 22.2%. TACE plus iodine-125 seed implantation did not show higher response rate (OR: 1.43, 95% CI: 0.96–2.15; P = 0.082) (Fig. 4). To determine the sources of heterogeneity, subgroup analysis was performed by dividing the patients according to the vascular invasion (VI) (with 16,22,23,25,26 or without 28). No heterogeneity was detected in VI group (I2 = 0%) (Fig. 5), indicating that VI contributed the most to study heterogeneity. Moreover, for patients with VI (portal vein tumor thrombosis (PVTT),16,22,25,27 inferior vena cava tumor thrombosis (IVCTT),23 inferior vena cava obstruction26), TACE plus iodine-125 seed implantation did not show higher response rate (OR: 1.16, 95% CI: 0.75–1.81; P = 0.504). Adverse events In iodine-125 seed implantation group, no serious adverse events or treatment-related deaths were reported. The most common adverse effects were postembolization syndromes, such as fever, mild nausea and mild abdominal pain. Granulocytopenia happened more frequently in the combination group (P < 0.001). The adverse events rate in each trial are summarized in Table 1.
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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Figure 2 Meta-analysis result of 1-year survival rate. Comparison of combined therapy with TACE alone for HCC. OR = odds ratio,
CI = confidence interval, TACE = transcatheter arterial chemoembolization
Figure 3 Meta-analysis result of 2-year survival rate. Comparison of combined therapy with TACE alone for HCC. OR = odds ratio,
CI = confidence interval, TACE = transcatheter arterial chemoembolization
Assessment of publication bias The Egger’s regression test was used for evaluating the risk of publication bias.17 The Egger’s regression test suggested that
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there was no obvious publication bias in the trials included in the current study (P = 0.527 for the 1-year survival, P = 0.286 for the response rate) (Supplemetary Fig. 2: A, B).
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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Figure 4 Meta-analysis result of response rate. Comparison of combined therapy with TACE alone for HCC. OR = odds ratio, CI = confidence
interval, TACE = transcatheter arterial chemoembolization
Discussion This meta-analysis provides evidence that TACE plus iodine-125 seed implantation significantly improved 1-, 2-year survival. TACE, as a palliative treatment for HCC, has become one of the most common interventional therapies, but it still has some limitations, and the outcomes are relatively poor.30,31 RT has not been commonly used to treat HCC, because conventional techniques are not able to adequately localize the radiation to the tumor. However, recent improvements in RT have allowed increased intra-tumor radiation and decreased radiation to the adjacent normal liver and organs, thereby reducing the rate of adverse events.32 Among the studies included in the current meta-analysis, 4 articles,16,23,25,29 reported that the 1-year survival rate in the combination therapy group showed no significant difference compared with TACE alone. However, according to the combined analysis, the 1-year survival rate increased in the combination group comparing to the TACE alone group. These different conclusions may derive from different baselines of characteristics in these studies: age, tumor size, with or without vascular invasion, AFP levels or the techniques of TACE. HCC patients with tumor thrombosis are regarded as advanced-stage patients. Sorafenib is the only recommended treatment for these patients.33,34 However, a study showed that for advanced but localized disease, sorafenib was associated with a longer median time to progression of only 1.8 months compared with HPB 2018, -, 1–8
placebo (5.8 vs. 4.0 months).35 Therefore, a more reliable local modality that can rapidly control vascular invasion to the portal vein is needed to improve clinical outcomes.36 Two studies had compared RT with or without TACE to sorafenib, and both of them showed that the OS of RT + TACE was longer compared to sorafenib treatment in advanced HCC patients.37,38 The objective response was comparative between the two groups. This might be explained as follows: 1), The vascular invasion (VI) is a mixture of tumor cells that respond to brachytherapy and a blood thrombus that does not. 2), When evaluating the lesion diameters of multiple lesions, the mRECIST criteria only include the three largest lesions regardless of their position. Patients with objective VI response had a longer survival time, perhaps owing to the amelioration of hepatofugal blood flow, which requires further investigation.16,23 The current results also indicate combination therapy associated with a longer survival outcome than TACE alone for HCC patients with vascular invasion (Supplementary Fig. 3). To the authors knowledge, no previous meta-analysis has reported the efficacy of TACE combined with iodine-125 seed implantation. While two meta-analyses,11,12 have reported that survival could be prolonged with adjuvant radiotherapy in patients with HCC compared with TACE alone. After TACE, iodine-125 seed implantation was performed under the guidance of ultrasound or CT in all included studies,
© 2018 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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Figure 5 Subgroup analysis result of response rate according to the vascular invasion (with or without). Comparison of combined therapy
with TACE alone for HCC. OR = odds ratio, CI = confidence interval, TACE = transarterial chemoembolization, VI = vascular invasion
Table 1 Adverse events in studies reported
Study
Arms
Patients n.
Fever%
Vomiting/Nausea%
Upper-abdominal pain%
Granulocyto-penia%
Yang Q et al.23
Experiment
33
65.2
71.7
63.0
NA
Control
28
63.2
73.7
57.9
NA
Experiment
66
10.1
4.5
NA
NA
Control
78
10.2
1.3
NA
NA
Experiment
26
73.0
50.0
NA
38.0
Control
30
70.0
53.0
NA
27.0
Experiment
56
NA
NA
NA
10.7
Control
50
NA
NA
NA
6.0
Experiment
21
76.2
90.5
80.9
NA
87.9
78.8
NA
0.434
<0.001
Li M et al.
24
Li C et al.25
Wu L et al.
27
Li S et al.29 Yang M et al.16
P-value
Control
33
78.8
Experiment
43
67.4 for all the adverse events
Control
42
59.5 for all the adverse events 0.315
0.852
NA: Not applicable.
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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and the iodine-125 seed was similar in these studies: the radioactivity of each iodine-125 seed is 25.9 MBq with a half-life of 59.4 days. Each seed can emit 27.4–31.5 keV X-ray and 35.5 keV g-ray. The half-value thickness of tissue for iodine-125 seeds is 17 mm, and the initial dose rate is 7 cGy/h. The effective irradiating range is 20 mm. Radioactive iodine-125 delivers g-rays which induce DNA strand breakage in cancer cells and then kill cancer cells. Iodine-125 seed implantation is superior to traditional radiation therapy: First, the half-value thickness of tissue is 17 mm in tissue, which makes high concentration of radiation rays in tumors while sparing normal tissues. Second, iodine-125 has a half-life of 59 days, which allows persistent effect of the seeds on tumors. Third, the procedure of implantation was plain and with less mild complications.39,40 This study may have several possible limitations: First, both RCTs and non-RCTs were included, which may have introduced selection bias and heterogeneity in outcomes reported. To evaluate this potential limitation, a subgroup analysis was performed depending on study design, and no evidence of high level of heterogeneity was found. Second, few studies showed the specific data of the adverse effects. Third, only two articles showed 2-year survival rate and the etiological factors of HCC (alcoholic hepatic disease, autoimmune liver disease, virus hepatitis, etc.) were not well considered in the included trials. Fourth, although idione125 seed has been widely used around the world, all the included studies were conducted in China, which may bring the regional bias. In conclusion, the treatment of TACE plus iodine-125 seed implantation can offer a more effective treatment and longer survival time for HCC patients than TACE alone.
2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F et al. (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132. 3. Llovet JM, Bruix J. (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37:429–442. 4. Llovet JM. (2005) Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 40:225–235. 5. Wang Y, Deng T, Zeng L, Chen W. (2016) Efficacy and safety of radiofrequency ablation and transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a meta-analysis. Hepatol Res 46:58–71. 6. Riemsma RP, Bala MM, Wolff R, Kleijnen J. (2013) Percutaneous ethanol injection for liver metastases. Cochrane Database Syst Rev 31. CD008717. 7. Wigg AJ, Palumbo K, Wigg DR. (2010) Radiotherapy for hepatocellular carcinoma: systematic review of radiobiology and modeling projections indicate reconsideration of its use. J Gastroenterol Hepatol 25:664 –671. 8. McGinn CJ, Ten Haken RK, Ensminger WD, Walker S, Wang S, Lawrence TS. (1998) Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. J Clin Oncol 16:2246–2252. 9. Merle P, Mornex F, Trepo C. (2009) Innovative therapy for hepatocellular carcinoma: three-dimensional high-dose photon radiotherapy. Cancer Lett 286:129–133. 10. Kang JK, Kim MS, Cho CK, Yang KM, Yoo HJ, Kim JH et al. (2012) Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 118:5424–5431. 11. Meng MB, Cui YL, Lu Y, She B, Chen Y, Guan YS et al. (2009) Transcatheter arterial chemoembolization in combination with radiotherapy for unresectable hepatocellular carcinoma: a systematic review and meta-analysis. Radiother Oncol 92:184–194. 12. Huo YR, Eslick GD. (2015) Transcatheter arterial chemoembolization plus radiotherapy compared with chemoembolization alone for hepa-
Grant support
tocellular carcinoma: a systematic review and meta-analysis. JAMA
This work was supported by grants from the Natural Science Foundation of China (81770615, 81700555, 81672882, 81502441 and 81502131) and the Science and Technology Program of Sichuan Province (2017SZ0003).
Oncol 1:756–765. 13. Nag S, DeHaan M, Scruggs G, Mayr N, Martin EW. (2006) Long-term follow-up of patients of intrahepatic malignancies treated with iodine125 brachytherapy. Int J Radiat Oncol Biol Phys 64:736–744. 14. Xiang GA, Chen KY, Wang HN, Xiao JF. (2010) Immunological influence of iodine-125 implantation in patients with hepatocellular carcinoma
Author contributions
resection [article in Chinese]. Nan Fang Yi Ke Da Xue Xue Bao 30:
Z.Z. conceived and designed the study. Z.Z. and X.W. searched the literature and extracted the data. Z.Z. and K.Y. wrote the manuscript. J.H and Y.Z. proofread the manuscript.
292–294. 15. Chen K, Chen G, Wang H, Li H, Xiao J, Duan X et al. (2014) Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial. J Hepatol 61:1304–1311.
Conflicts of interest None declared.
16. Yang M, Fang Z, Yan Z, Luo J, Liu L, Zhang W et al. (2014) Transarterial chemoembolisation (TACE) combined with endovascular implantation of an iodine-125 seed strand for the treatment of hepatocellular carci-
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42:802–805. 29. Li S, He X, Dang L, Xu F, Fang J, Li F et al. (2018) Efficacy of 125I versus Non-125I combined with transcatheter arterial chemoembolization for
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Supplementary data related to this article can be found at https://doi.org/10. 1016/j.hpb.2018.03.015.
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
https://doi.org/10.1016/j.hpb.2018.03.015
REVIEW ARTICLE
Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis Ze-xin Zhu1, Xiao-xue Wang2, Ke-fei Yuan1, Ji-wei Huang1 & Yong Zeng1 1 2
Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, 610041, China, and Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, 610041, China
Abstract Background: Hepatocellular carcinoma (HCC) is the most common malignancy in liver. Transarterial chemoembolization (TACE) is recommended as an effective treatment in advanced HCC patients. Recent studies showed iodine-125 seed (a low-energy radionuclide) can provide long-term local control and increase survival for HCC patients. The aim of the study was to evaluate the outcome of TACE plus iodine-125 seed in comparison with TACE alone for HCC. Methods: A comprehensive search of studies among PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted with published date from the earliest to January 10th, 2018. No language restrictions were applied, while only prospective randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) were eligible for a full-text review. The primary outcome was overall survival (OS), response rate (the rate of partial atrophy or complete clearance of the tumor lesion) and adverse events (AEs). The odds ratios (ORs) were combined using either fixed-effects model or random-effects model. All statistical analyses were performed using the Stata 12.0 software. Results: 9 studies were included, involving 894 patients. Among them, 473 patients received combined therapy of TACE plus iodine-125 implantation, compared with 421 patients with TACE alone. Patients receiving combined therapy of TACE plus iodine-125 showed significantly improvement in 1-year OS (OR = 4.47, 95% confidence intervals (CI): 2.97–6.73; P < 0.001), 2-year OS (OR = 4.72, 95% CI: 2.63–8.47; P < 0.001). No significant publication bias was observed in any of the measured outcomes. Conclusions: Based on these findings, TACE plus iodine-125 implantation achieves better clinical efficacy compared with TACE alone in the treatment of HCC. Received 4 February 2018; accepted 28 March 2018
Correspondence Yong Zeng; Ke-fei Yuan; Ji-wei Huang, Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu 610041, China. E-mails: [email protected] (Y. Zeng); [email protected] (K.-f. Yuan); [email protected] (J.-w. Huang)
Introduction Hepatocellular carcinoma (HCC) is the most common malignancy in liver. Its global incidence has been reported to be on the rise and is predicted to exceed a million patients per year by 2025.1 According to the recent statistics, HCC is the 4th most commonly diagnosed cancers among men, and the 4th leading causes of cancer death among both men and women in China.2 Liver transplantation (LT) and hepatic resection are possible
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curative treatments for HCC patients. Although the improvements in surgical technology had made more HCC tumors resectable, <40% of patients are diagnosed at an early stage and suitable for surgical resection.3 Transarterial chemoembolization (TACE) has been demonstrated to be an effective treatment in improving survival for patients with advanced HCC (stage B/C under the Barcelona Clinic Liver Cancer (BCLC) system).3 The TACE protocol has been
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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updated several times.4 The optimal combination of TACE with anti-tumor agent and adjuvant treatments are still are still evolving. TACE combined with other treatments, such as radiofrequency ablation or percutaneous ethanol injection, have been shown to improve overall survival as compared to TACE alone.5,6 Traditionally, radiotherapy (RT) plays a limited role in the treatment of HCC.7,8 However, recent studies showed that TACE in combination with radiotherapy was more therapeutically beneficial than TACE alone for treating HCC patients.9,10 Consistently, two meta-analyses also showed more favorable result.11,12 According to Nag S et al.,13 iodine-125 seed (a low-energy radionuclide), can provide long-term local control and increased survival for HCC patients. Meanwhile, another study also revealed that iodine-125 seed implantation can strongly stimulate the anti-tumor immune response in HCC patients.14 Moreover, two recent studies indicated that the combination therapy with iodine-125 seed implantation was superior to monotherapy in the treatment of HCC.15,16 However, no largescale multicenter clinical research has been reported so far. The aim of this review was to provide a rigorous summary by pooling the results of the currently available data on the survival outcomes of HCC patients who underwent TACE plus iodine125 seed implantation or TACE alone.
Materials and methods The process of the meta-analysis was carried out according to the Cochrane Collaboration recommendations.17 The analysis results were reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.18 Search strategy A comprehensive search of the PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted. The combination of free-text words and MeSH terms used were as follows: “((125) or (iodine seed) or (radiotherapy)) AND ((transcatheter arterial chemoembolization) or TACE or TAE) AND ((liver cancer) or (hepatocellular carcinoma) or (HCC))”. The sensitive searching of clinical trials was under Cochrane’s recommendation.19 The search included literature published until January 10th, 2018 with no lower date limit. No language restrictions were applied, but only prospective randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) were eligible for a full-text review. References of all the main review articles on this topic were analyzed manually to identify any relevant citations missed on the initial search. Two independent researchers performed search. Including and excluding criteria Publications complied with the following criteria were accepted: 1) HCC diagnosed by computed tomography (CT), magnetic resonance imaging (MRI) or pathology; 2) prospective HPB 2018, -, 1–8
randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs); 3) published trials that included a treatment group receiving TACE plus iodine-125 seed implantation and a control group receiving TACE alone; and 4) reported survival rate or tumor response rate on at least 1-year follow-up, while the criteria for tumor response must be described clearly. Abstracts, letters, case reports, and studies without control groups were excluded. In treatment centers with multiple publications, the most recent and/or largest publication was included. Data extraction Data extraction was performed using a standardized form, two authors (Zhu Z and Wang X) collected information regarding study characteristics (such as author name, year of publication, study design, sample size, length of follow-up), intervention characteristics (such as with or without iodine-125, drugs of TACE treatments); patients’ characteristics (such as age, gender, ChildPugh Class, with or without tumor thrombosis); and mortality outcomes (that is, number of deaths and patients included for analyses in each treatment group). Tumor response was evaluated by the change in tumor size on abdominal CT and MRI before and after treatment. Tumor response rates would be recorded according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) guidelines for HCC. Complete response (CR) was defined as complete clearance of the lesion after treatment; partial response (PR) was defined as 30% decrease in the diameters of target lesions; progressive disease (PD) was defined as 20% increase in the summed diameters of target lesions, taking the smallest summed value recorded since treatment as reference; stable disease (SD) was the summed value lies between PD and PR. The response rate was the sum of CR and PR.20 Quality assessment The risk of bias in RCTs was assessed following Cochrane recommendations, considering random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting. Each category was assessed as low, unclear or high risk of bias and summarized in a table with a plus, question mark or minus, respectively.19 The quality of non-RCTs was assessed using the NewcastleOttawa Scale.21 This scale assesses risk of bias in three domains: 1, selection of the study groups (including representativeness of exposed cohort, selection of non exposed, ascertainment of exposure, outcome not present at start); 2, comparability of groups; and 3, ascertainment of exposure and outcome (including assessment of outcome, adequate follow-up length, adequacy of follow-up). A study can be rated 0–9 stars based on these criteria. Studies with scores >7 were considered as having a low risk of bias, scores of 4–6 as having a moderate risk of bias, and scores <4 as having a high risk of bias. Follow-up was adequate if the median or mean follow-up was in excess of 2-year.
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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Statistical analyses The primary outcome was the overall survival (OS) and the response rate (the rate of partial atrophy or complete clearance of the tumor lesion). Pooled ORs with 95%CI were calculated using either the fixed-effects model or random-effects model. For each meta-analysis, the c2 and I2 statistics were first calculated to assess the heterogeneity of the included studies. P < 0.1 and I2 > 50% were considered significant. For P < 0.1 and I2 > 50%, the random-effects model was used. Otherwise, data were assessed using the fixed-effects model. The significance of the pooled ORs was assessed by the Z-test. P < 0.05 was considered statistically significant. Publication bias was evaluated by Egger’s regression, P < 0.05 were considered as significantly publication bias.17 All statistical analyses were performed using the Stata 12.0 (Stata Corporation, College Station, TX, USA).
Results Literature search and description of the studies The results of the search strategy are shown in Fig. 1. We have searched a total of 471 studies. Finally, 9 studies were included for analysis,16,22–29 including 2 randomized controlled trials (RCTs),16,28 and 7 non-RCTs.22–27,29 These studies were published from 2008 to 2017 and all of them investigated the therapy of TACE plus iodine-125 seed implantation. A total of 894 patients were included in these studies. Among them, 473 (52.9%) patients were carried with TACE plus iodine-125 seed implantation therapy, while 421 (47.1%) patients received TACE alone. Individual study data are shown in Supplementary Table 1. Generally, Lipiodol was mixed with the drugs at a uniform
Figure 1 Identification of eligible studies from databases
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dosage or a dosage calculated according to the tumor size before the procedure. The dosage of Lipiodol ranged from 2 to 20 mL. Iodine-125 seed implantation was performed under the guidance of ultrasound or Computed Tomography (CT) with local anesthesia. Patients in the test group underwent iodine-125 seed implantation therapy after TACE. Quality assessment The overall risk of all types of bias in the RCTs was generally low to unclear (Supplementary Fig. 1A and 1B). Non-RCT Studies included were all 6 stars or above by the Newcastle Ottawa scale (Supplementary Table 2). Overall survival rate 1-, 2-year survival rate were compared. The heterogeneity was low among the trials. Seven studies,16,22–25,27,29 reported 1-year survival. TACE plus iodine-125 seed implantation (427 (54.6%) patients) was associated with a higher one-year survival rate compared with TACE alone (355 (45.4%) patients) (odds ratio (OR): 4.47, 95% confidence intervals (CI): 2.97–6.73; P < 0.001). The total survival benefit of iodine-125 seed implantation therapy is significant (Fig. 2). Two-year survival rate was reported in 2 studies,22,24 TACE plus iodine-125 seed implantation (248 (59.0%) patients) has a higher two-year survival rate compared with TACE alone (172 (41.0%) patients) (OR: 4.72, 95% CI: 2.63–8.47; P < 0.001) (Fig. 3). Response rate (CR + PR) 6 studies,16,22,23,25,26,38 compared the response rate, including 590 patients. They all followed the RECIST after treatment. The result of heterogeneity tests among trials was P = 0.267, I2 = 22.2%. TACE plus iodine-125 seed implantation did not show higher response rate (OR: 1.43, 95% CI: 0.96–2.15; P = 0.082) (Fig. 4). To determine the sources of heterogeneity, subgroup analysis was performed by dividing the patients according to the vascular invasion (VI) (with 16,22,23,25,26 or without 28). No heterogeneity was detected in VI group (I2 = 0%) (Fig. 5), indicating that VI contributed the most to study heterogeneity. Moreover, for patients with VI (portal vein tumor thrombosis (PVTT),16,22,25,27 inferior vena cava tumor thrombosis (IVCTT),23 inferior vena cava obstruction26), TACE plus iodine-125 seed implantation did not show higher response rate (OR: 1.16, 95% CI: 0.75–1.81; P = 0.504). Adverse events In iodine-125 seed implantation group, no serious adverse events or treatment-related deaths were reported. The most common adverse effects were postembolization syndromes, such as fever, mild nausea and mild abdominal pain. Granulocytopenia happened more frequently in the combination group (P < 0.001). The adverse events rate in each trial are summarized in Table 1.
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Figure 2 Meta-analysis result of 1-year survival rate. Comparison of combined therapy with TACE alone for HCC. OR = odds ratio,
CI = confidence interval, TACE = transcatheter arterial chemoembolization
Figure 3 Meta-analysis result of 2-year survival rate. Comparison of combined therapy with TACE alone for HCC. OR = odds ratio,
CI = confidence interval, TACE = transcatheter arterial chemoembolization
Assessment of publication bias The Egger’s regression test was used for evaluating the risk of publication bias.17 The Egger’s regression test suggested that
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there was no obvious publication bias in the trials included in the current study (P = 0.527 for the 1-year survival, P = 0.286 for the response rate) (Supplemetary Fig. 2: A, B).
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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Figure 4 Meta-analysis result of response rate. Comparison of combined therapy with TACE alone for HCC. OR = odds ratio, CI = confidence
interval, TACE = transcatheter arterial chemoembolization
Discussion This meta-analysis provides evidence that TACE plus iodine-125 seed implantation significantly improved 1-, 2-year survival. TACE, as a palliative treatment for HCC, has become one of the most common interventional therapies, but it still has some limitations, and the outcomes are relatively poor.30,31 RT has not been commonly used to treat HCC, because conventional techniques are not able to adequately localize the radiation to the tumor. However, recent improvements in RT have allowed increased intra-tumor radiation and decreased radiation to the adjacent normal liver and organs, thereby reducing the rate of adverse events.32 Among the studies included in the current meta-analysis, 4 articles,16,23,25,29 reported that the 1-year survival rate in the combination therapy group showed no significant difference compared with TACE alone. However, according to the combined analysis, the 1-year survival rate increased in the combination group comparing to the TACE alone group. These different conclusions may derive from different baselines of characteristics in these studies: age, tumor size, with or without vascular invasion, AFP levels or the techniques of TACE. HCC patients with tumor thrombosis are regarded as advanced-stage patients. Sorafenib is the only recommended treatment for these patients.33,34 However, a study showed that for advanced but localized disease, sorafenib was associated with a longer median time to progression of only 1.8 months compared with HPB 2018, -, 1–8
placebo (5.8 vs. 4.0 months).35 Therefore, a more reliable local modality that can rapidly control vascular invasion to the portal vein is needed to improve clinical outcomes.36 Two studies had compared RT with or without TACE to sorafenib, and both of them showed that the OS of RT + TACE was longer compared to sorafenib treatment in advanced HCC patients.37,38 The objective response was comparative between the two groups. This might be explained as follows: 1), The vascular invasion (VI) is a mixture of tumor cells that respond to brachytherapy and a blood thrombus that does not. 2), When evaluating the lesion diameters of multiple lesions, the mRECIST criteria only include the three largest lesions regardless of their position. Patients with objective VI response had a longer survival time, perhaps owing to the amelioration of hepatofugal blood flow, which requires further investigation.16,23 The current results also indicate combination therapy associated with a longer survival outcome than TACE alone for HCC patients with vascular invasion (Supplementary Fig. 3). To the authors knowledge, no previous meta-analysis has reported the efficacy of TACE combined with iodine-125 seed implantation. While two meta-analyses,11,12 have reported that survival could be prolonged with adjuvant radiotherapy in patients with HCC compared with TACE alone. After TACE, iodine-125 seed implantation was performed under the guidance of ultrasound or CT in all included studies,
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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Figure 5 Subgroup analysis result of response rate according to the vascular invasion (with or without). Comparison of combined therapy
with TACE alone for HCC. OR = odds ratio, CI = confidence interval, TACE = transarterial chemoembolization, VI = vascular invasion
Table 1 Adverse events in studies reported
Study
Arms
Patients n.
Fever%
Vomiting/Nausea%
Upper-abdominal pain%
Granulocyto-penia%
Yang Q et al.23
Experiment
33
65.2
71.7
63.0
NA
Control
28
63.2
73.7
57.9
NA
Experiment
66
10.1
4.5
NA
NA
Control
78
10.2
1.3
NA
NA
Experiment
26
73.0
50.0
NA
38.0
Control
30
70.0
53.0
NA
27.0
Experiment
56
NA
NA
NA
10.7
Control
50
NA
NA
NA
6.0
Experiment
21
76.2
90.5
80.9
NA
87.9
78.8
NA
0.434
<0.001
Li M et al.
24
Li C et al.25
Wu L et al.
27
Li S et al.29 Yang M et al.16
P-value
Control
33
78.8
Experiment
43
67.4 for all the adverse events
Control
42
59.5 for all the adverse events 0.315
0.852
NA: Not applicable.
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Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015
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and the iodine-125 seed was similar in these studies: the radioactivity of each iodine-125 seed is 25.9 MBq with a half-life of 59.4 days. Each seed can emit 27.4–31.5 keV X-ray and 35.5 keV g-ray. The half-value thickness of tissue for iodine-125 seeds is 17 mm, and the initial dose rate is 7 cGy/h. The effective irradiating range is 20 mm. Radioactive iodine-125 delivers g-rays which induce DNA strand breakage in cancer cells and then kill cancer cells. Iodine-125 seed implantation is superior to traditional radiation therapy: First, the half-value thickness of tissue is 17 mm in tissue, which makes high concentration of radiation rays in tumors while sparing normal tissues. Second, iodine-125 has a half-life of 59 days, which allows persistent effect of the seeds on tumors. Third, the procedure of implantation was plain and with less mild complications.39,40 This study may have several possible limitations: First, both RCTs and non-RCTs were included, which may have introduced selection bias and heterogeneity in outcomes reported. To evaluate this potential limitation, a subgroup analysis was performed depending on study design, and no evidence of high level of heterogeneity was found. Second, few studies showed the specific data of the adverse effects. Third, only two articles showed 2-year survival rate and the etiological factors of HCC (alcoholic hepatic disease, autoimmune liver disease, virus hepatitis, etc.) were not well considered in the included trials. Fourth, although idione125 seed has been widely used around the world, all the included studies were conducted in China, which may bring the regional bias. In conclusion, the treatment of TACE plus iodine-125 seed implantation can offer a more effective treatment and longer survival time for HCC patients than TACE alone.
2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F et al. (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132. 3. Llovet JM, Bruix J. (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37:429–442. 4. Llovet JM. (2005) Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 40:225–235. 5. Wang Y, Deng T, Zeng L, Chen W. (2016) Efficacy and safety of radiofrequency ablation and transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a meta-analysis. Hepatol Res 46:58–71. 6. Riemsma RP, Bala MM, Wolff R, Kleijnen J. (2013) Percutaneous ethanol injection for liver metastases. Cochrane Database Syst Rev 31. CD008717. 7. Wigg AJ, Palumbo K, Wigg DR. (2010) Radiotherapy for hepatocellular carcinoma: systematic review of radiobiology and modeling projections indicate reconsideration of its use. J Gastroenterol Hepatol 25:664 –671. 8. McGinn CJ, Ten Haken RK, Ensminger WD, Walker S, Wang S, Lawrence TS. (1998) Treatment of intrahepatic cancers with radiation doses based on a normal tissue complication probability model. J Clin Oncol 16:2246–2252. 9. Merle P, Mornex F, Trepo C. (2009) Innovative therapy for hepatocellular carcinoma: three-dimensional high-dose photon radiotherapy. Cancer Lett 286:129–133. 10. Kang JK, Kim MS, Cho CK, Yang KM, Yoo HJ, Kim JH et al. (2012) Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 118:5424–5431. 11. Meng MB, Cui YL, Lu Y, She B, Chen Y, Guan YS et al. (2009) Transcatheter arterial chemoembolization in combination with radiotherapy for unresectable hepatocellular carcinoma: a systematic review and meta-analysis. Radiother Oncol 92:184–194. 12. Huo YR, Eslick GD. (2015) Transcatheter arterial chemoembolization plus radiotherapy compared with chemoembolization alone for hepa-
Grant support
tocellular carcinoma: a systematic review and meta-analysis. JAMA
This work was supported by grants from the Natural Science Foundation of China (81770615, 81700555, 81672882, 81502441 and 81502131) and the Science and Technology Program of Sichuan Province (2017SZ0003).
Oncol 1:756–765. 13. Nag S, DeHaan M, Scruggs G, Mayr N, Martin EW. (2006) Long-term follow-up of patients of intrahepatic malignancies treated with iodine125 brachytherapy. Int J Radiat Oncol Biol Phys 64:736–744. 14. Xiang GA, Chen KY, Wang HN, Xiao JF. (2010) Immunological influence of iodine-125 implantation in patients with hepatocellular carcinoma
Author contributions
resection [article in Chinese]. Nan Fang Yi Ke Da Xue Xue Bao 30:
Z.Z. conceived and designed the study. Z.Z. and X.W. searched the literature and extracted the data. Z.Z. and K.Y. wrote the manuscript. J.H and Y.Z. proofread the manuscript.
292–294. 15. Chen K, Chen G, Wang H, Li H, Xiao J, Duan X et al. (2014) Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: a prospective randomized controlled trial. J Hepatol 61:1304–1311.
Conflicts of interest None declared.
16. Yang M, Fang Z, Yan Z, Luo J, Liu L, Zhang W et al. (2014) Transarterial chemoembolisation (TACE) combined with endovascular implantation of an iodine-125 seed strand for the treatment of hepatocellular carci-
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Supplementary data related to this article can be found at https://doi.org/10. 1016/j.hpb.2018.03.015.
© 2018 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
Please cite this article in press as: Zhu Z-x, et al., Transarterial chemoembolization plus iodine-125 implantation for hepatocellular carcinoma: a systematic review and meta-analysis, HPB (2018), https://doi.org/10.1016/j.hpb.2018.03.015