TransArterial ChemoEmbolization (TACE) with platinum versus anthracyclines for hepatocellular carcinoma: A meta-analysis

International Journal of Surgery 53 (2018) 151–158

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International Journal of Surgery journal homepage: www.elsevier.com/locate/ijsu

Review

TransArterial ChemoEmbolization (TACE) with platinum versus anthracyclines for hepatocellular carcinoma: A meta-analysis

T

Mengdie Zhaoa,1, Ping Xiangb,1, Hao Jianga,∗ a b

Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, PR China Central Laboratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, PR China

A R T I C LE I N FO

A B S T R A C T

Keywords: HCC TACE Platinum Anthracyclines Meta-analysis

Objective: To determine the clinical efficacy of TACE with platinum versus anthracyclines for hepatocellular carcinoma (HCC) patients using a meta-analysis. Methods: We conducted a systematic review of the literature in PubMed, Embase, and the Cochrane Library database to discover relevant randomized controlled trials (RCTs) and observational studies. Data on therapeutic response, adverse event and overall survival rate from studies that compared TACE with platinum versus anthracyclines for HCC patients was extracted for pooled estimation. Subgroup analysis was used if further investigation was needed. The Q statistic and the I2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Egger's test. Results: Four RCTs and seven observational studies containing 1405 patients were included in this meta-analysis. After comparing RCTs and observational studies separately, the pooled estimation results indicated that no significant difference existed between platinum and anthracyclines regarding therapeutic response, adverse event and overall survival rate. Furthermore, Egger's test revealed bias in pooled estimation of survival rate among RCTs. Conclusions: Based on current results, we concluded that TACE with platinum revealed similar clinical efficacy compared with anthracyclines. And more relative studies in this field were expected in the future.

1. Introduction Hepatocellular carcinoma (HCC) is one of the most common malignancies world-wide and third global leading cause of cancer-related death [1,2]. Although HCC management continues to develop [3,4], its therapeutic effect and actions at the molecular level are still incompletely understood. Moreover, HCC is most frequently diagnosed at an intermediate or advanced stage and a substantial proportion of patients have poor liver reserve and/or compromised portal vein flow; consequently, untreated unresectable HCC has a poor prognosis [5]. For unresectable HCC or preoperative treatment, transarterial chemoembolization (TACE) is an established local therapy in patients with advanced cirrhosis and confers significant survival benefits [6,7]. It is the current standard of care for patients with large or multinodular HCC, preserved liver function, absence of cancer-related symptoms, and no evidence of vascular invasion or extrahepatic spread [8,9]. Furthermore, in clinical practice, many patients carrying contraindications to curative approaches are treated with TACE. Therefore, TACE is also a very effective alternative therapy for patients with advanced HCC. ∗

1

Technically TACE is the intra-arterial injection of a chemotherapeutic drug such as platinum or anthracyclines followed by embolization of the blood vessel will result in a strong cytotoxic effect enhanced by ischemia. For patients who undergo TACE, application of different anti-cancer agents may bring different clinical efficacy. It is known that anti-cancer agents are commonly used for TACE yet their clinical comparisons are reported contradictorily. Anthracyclines are a class of anti-cancer drugs, including doxorubicin, epirubicin and idarubicin, which were initially described as antibiotics. They have been used as anti-cancer therapy for many years and now have a vital role in the treatment of leukemia, lymphoma, uterine, ovarian, and breast malignancies [10–12]. The major anti-tumor mechanism is by inhibiting DNA and RNA synthesis by intercalating the base pairs of the DNA/RNA strand, thus preventing replication of rapidly dividing cancer cells [13]. On the other hand, platinum-based anti-cancer drugs including cisplatin, miriplatin, and lobaplatin have entered clinical application globally. However, their tumor selectivity is quite poor. Its systemic toxicity and drug resistance are major drawbacks with platinum drugs. For this reason, they are often selected for local therapy

Corresponding author. E-mail address: [email protected] (H. Jiang). Both authors contributed equally to this work.

https://doi.org/10.1016/j.ijsu.2018.03.049 Received 16 November 2017; Received in revised form 17 March 2018; Accepted 21 March 2018 Available online 27 March 2018 1743-9191/ © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

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Fig. 1. Flow diagram of the process of including and excluding studies for this meta-analysis.

survival rate). The exclusion criteria eliminated studies with the following characteristics: (1) without control group; (2) no available data; (3) limitation to animals or cells; (4) reviews, study protocols, comments, or case reports.

such as TACE. For TACE, platinum and anthracyclines are often used as anti-cancer agents and usually prepared as emulsions mixed with iodized oil or drug-eluting beads before intraarterial administration [14,15]. However, local control effects of TACE for HCC with platinum or anthracyclines still remains uncertain. To further understand the clinical efficacy of TACE with platinum versus anthracyclines, we conducted a quantitative meta-analysis to compare platinum and anthracyclines. The purpose of this study is to provide related objective evidences for clinical decision-making.

2.3. Data extraction and quality assessment

This review was conducted using a pre-defined protocol in accordance with both PRISMA and MOOSE guidelines [16,17]. To avoid local publication bias and ensure the authenticity of included studies, we only conducted our retrieval in global recognized database (PubMed, EMBASE, and Cochrane Central). The search strings were based on MeSH terms, including “TACE,” “transarterial chemoembolization,” “HCC,” or “hepatocellular carcinoma.” Different combinations of these terms were used for the searches and were expanded to relevant topics to avoid neglecting eligible studies (Example in Supplementary Table S1). We did not apply any language, publication date, or publication status restrictions.

Full manuscripts of eligible studies were addressed and detailed reviewed. General information including author's name, year of publication and intervention was recorded into a pre-designed electronic data sheet. The parametric data including therapeutic response rate, adverse events and overall survival rate was collected for quantitative analyzing. The Cochrane risk of bias assessment tool [18] was used to assess the bias of each included RCT by the following criteria: (1) free of selection bias, (2) free of performance bias, (3) free of detection bias, (4) free of attrition bias, (5) free of reporting bias, and (6) free of other bias. For the evaluation of observational studies, Newcastle-Ottawa Quality Assessment Scale [19] was selected to assess the methodological quality. Three major components of each study were examined: (1) patient selection; (2) the comparability of the intervention and the observation groups; and (3) outcome assessment. Each item was evaluated and scored with stars. The final star calculation of each included study was presented.

2.2. Study selection and eligibility criteria

2.4. Statistical analysis

The studies included in our meta-analysis satisfied all the following criteria: (1) randomized controlled trial (RCT), or observational study; (2) clearly diagnosed HCC; (3) application of platinum versus anthracycline in TACE being the only intervention; (4) provision of available parametric data (including response rate, adverse events, and overall

In this research, we included both RCTs and observational studies. And data analyzing would be separated according to study type. We aimed to determine the clinical efficacy and safety of TACE with platinum versus anthracyclines for HCC patients. Thus three main outcomes (therapeutic response rate, adverse events and overall survival

2. Methods 2.1. Data sources and search strategy

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3.3. Heterogeneity and publication bias

rate) were compared by quantitative pooled estimation. All parametric data was provided as dichotomous variable. The relative risk ratio (RR) of dichotomous variables and its 95% confidence interval (CI) were calculated. Heterogeneity (I2) was used to estimate a data model. We estimated the pooled estimates of the risk ratio. The relevant 95% confidence interval (CI) that used fixed (I2 < 50%) or random (I2 > 50%) effects models depended on the heterogeneity of the included trials. Publication bias was presented using Egger's regression plot and was quantitatively analyzed by Egger's test [20]. If there was a significant risk of bias, the source of bias had to be explored or discussed. In addition, if necessary, sensitivity or subgroup analysis would be conducted. All of the data manipulation and statistical analyses of this study were conducted using the Stata software package (version 12.0).

We chose 3 parametric data to evaluate the clinical efficacy using either platinum or anthracyclines during TACE. We separately compared therapeutic response rate, adverse events and overall survival rate regarding RCTs and observational studies. The obvious heterogeneity was not detected except the comparison of adverse events among observational studies (I2 = 50.6%) (Fig. 3B). Thus we deemed that the included data was basically consistent. Moreover, as per the above description, we measured the publication bias based on Egger's test (Supplementary Fig. S1- S3), which confirmed that no obvious publication bias existed, except for survival rate from 2 RCTs (t = 5.27, P = 0.002) (Supplementary Fig. S2A). 3.4. Subgroup analysis

3. RESULTS

According to our inclusion criteria, we selected 4 RCTs and 7 observational studies for this meta-analysis. For comparison of therapeutic response rate, 4 RCTs and 5 observational studies provided related data. We also performed related subgroup analysis according to nations, medical applications and different standards. We found that no significant difference existed among the Japanese studies or the other nations. Moreover, no obvious difference was detected based on different combinations of medical applications. For subgroup classification of evaluation standards, we divided 2 subgroups according to Japanese [32] and European standards [33]. Similarly, no difference could be detected in each subgroup (Table 2). On the other hand, we also conducted subgroup analysis of adverse events according to nations and medical applications, which exhibited no significant difference between platinum and anthracyclines (Table 3). What's more, we also performed related subgroup analysis according to Common Terminology Criteria for Adverse Events (CTCAE) standards or others. In addition, subgroup analysis of degrees according to CTCAE standards was also presented. But neither of them exhibited difference between platinum and anthracyclines (Table 3). For the record, we did not perform any subgroup analysis of survival rate due to insufficient studies.

3.1. Study characteristics and quality After detailed evaluation, 11 articles (4 RCTs and 7 observational studies) [21–31] containing 1405 patients were included for analysis (Fig. 1). Nine were reported from Asia and the other 2 were from Europe. The parametric data of response rate, adverse events and overall survival rate were respectively provided by 9, 7, and 6 articles (Table 1). For quality assessment, no obvious publication bias or particular low quality literature existed (Supplementary Table S2).

3.2. The clinical efficacy of platinum during TACE seemed to be similar with anthracyclines We conducted a quantitative data synthesis from statistical pooling using fixed-effects modeling to compare the therapeutic response rate. Both in RCTs (Fig. 2A) and observational studies (Fig. 2B), the results revealed that application of platinum did not enhance the therapeutic response rate compared with anthracyclines (Test P = 0.290 and 0.844, respectively). Furthermore, for the safety evaluation, we compared the adverse events from 3 RCTs (Fig. 3A) and 4 observational studies (Fig. 3B). We found no significant difference between platinum and anthracyclines (Test P = 0.833 and 0.362, respectively). For long-term outcomes, overall survival rate was selected to be analyzed both in RCTs and non-RCTs. 2 RCTs provided 1-year survival rate and we chose 3-, 6-, 9-, and 12-month for pooled estimation (Fig. 4A). Meanwhile, 3 observational studies provided 3-year overall survival rate and 1-, 2-, and 3-year survival rate were selected for data synthesis (Fig. 4B). After quantitative analyzing, the result showed that no significant different impacts on survival rate between platinum and anthracyclines (Test P = 0.860 and 0.305, respectively).

4. Discussion Although TACE is usually considered as first-line treatment for intermediate unresectable HCC, it remains an heterogeneous procedure widely varying in terms of drugs injected, embolic agents and treatment schedules [34,35]. Therefore, the best single or combination drug regime should be administered. Theoretically, microenvironment has a crucial role in the response of cancer cells to local therapy. And local application of anti-cancer agents may exhibit direct and better pharmacological benefits. Thus it is important to confirm whether different anti-cancer drugs used in TACE induce different clinical effects in HCC patients. To our best knowledge, this study is the first quantitative analysis to compare TACE with platinum versus anthracyclines for HCC. After

Table 1 Characteristics of the included trials. Author

Country

Year

Study Type

Intervention

Sample Size

Available Parameters

Ikeda Kubota Sahara Wang Arabi Aramaki Handa Vericat Wiggermann Yamanaka Yodono

Japan Japan Japan China Saudi Arabia Japan Japan Spain Germany Japan Japan

2017 2017 2010 2014 2017 2012 2014 2015 2011 2011 2011

RCT RCT RCT RCT Observational Observational Observational Observational Observational Observational Observational

Epirubicin vs. Miriplatin Epirubicin vs. Miriplatin Epirubicin vs. Cisplatin Pirarubicin vs. Lobaplatin Doxorubicin vs. Cisplatin Epirubicin vs. Miriplatin Epirubicin vs. Miriplatin Doxorubicin vs. Cisplatin Epirubicin vs. Cisplatin Epirubicin vs. Cisplatin Epirubicin vs. Cisplatin

123/124 99/99 16/12 83/90 35/19 42/27 97/124 30/30 22/22 99/32 106/96

Response Rate; Adverse Events; Survival Rate Response Rate; Adverse Events Response Rate; Adverse Events Response Rate; Survival Rate Response Rate; Adverse Events Response Rate; Adverse Events; Survival Rate Response Rate Adverse Events; Survival Rate Response Rate; Adverse Events; Survival Rate Response Rate Survival Rate

Study Study Study Study Study Study Study

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Fig. 2. Pooled estimation of the therapeutic response rate after application platinum versus anthracyclines in TACE regarding (A) RCTs or (B) observational studies.

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Fig. 3. Meta-analysis of adverse events between TACE with platinum and anthracyclines regarding (A) RCTs or (B) observational studies.

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Fig. 4. Meta-analysis of overall survival rate between platinum versus anthracyclines in TACE regarding (A) RCTs or (B) observational studies.

platinum chemoembolization with respect to anthracyclines in HCC patients. In the last decade, chemotherapy regimens and therapeutic plans with TACE have been developed. Agents mixed with lipiodol or drug-eluting beads are commonly used. However, the clinical effects do not seem to be significantly improved [37,38]. Accordingly, we can deduce that induced tissue hypoxia caused by embolism may be the more effective treatment and addition of anti-cancer drugs a lesser factor. Thereby selection of drug types may be not the key factor for the clinical effects after TACE. A previous RCT on beads loaded with doxorubicin versus beadblock without any anti-cancer agents illustrated that beads embolism with anti-cancer drugs was not superior than that without anti-cancer agent [39]. This may further prove that vascular embolism is the decisive factor and the role and effects of anti-cancer drugs in TACE may be over-estimated. However, alternative research argues that beads loaded with doxorubicin presents a better local response than that without drugs [40]. But it exhibited no benefit on adverse events and survival rate. Thereby this issue is still in need of further discussion in the future. What's more, TACE induced tumor hypoxia environment may promote the alteration of tumor both microenvironment and metabolism, potentiating or altering the effects of chemotherapy agents. In addition, clinical effect of local

including 4 RCTs and 7 observational studies, we compared therapeutic response rate, adverse events and survival rate to evaluate the treatment efficacy, safety and long-term outcome. However, according to our objective results, no significant difference was detected after comparing each parametric data, which meant platinum and anthracyclines exhibited similar clinical value. In addition, to make further exploration, we also performed subgroup analysis regarding nations, medications, and so on. None revealed a difference between platinum and anthracyclines. Using Egger's test no obvious bias was found in respective results (Supplementary Fig. S3A). This may be due to insufficient studies or Asian local publication bias. But in general, our results considered to be objective and reliable. TACE was used to block the blood supply of the tumor by embolizing main arterial vessels with embolic agents. Meanwhile, theoretically, it may bring better clinical efficacy if chemotherapeutic drugs were loaded on embolic agents. In other words, embolic agents can provide tumor hypoxia environment and chemotherapeutic drugs may treat lesions with a further step [36]. Based on these facts, relative clinical trails of different chemotherapeutic drugs used in TACE were reported but the contradictions between platinum and anthracyclines were still remained. However, our results stand for a non-superiority of

Table 2 Subgroup analysis of therapeutic response rate according to certain factors. Subcategory

Nations Japan Others Medications Epirubicin vs. Miriplatin Epirubicin vs. Cisplatin Others Standards Europe Japan

Study type

No. of studies

Pooled estimation

Test of heterogeneity

P value

95% Conf. Intervval

P value

Chi-squared

I-squared

RCT Non-RCT RCT Non-RCT

3 3 1 2

0.593 0.559 0.090 0.930

0.932 0.823 0.982 0.883

1.130 1.111 1.279 1.146

0.937 0.729 – 0.841

0.41 0.63 – 0.35

0.0% 0.0% – 0.0%

RCT Non-RCT RCT Non-RCT RCT Non-RCT

2 2 1 2 1 1

0.726 0.835 0.657 0.610 0.090 0.519

0.913 0.843 0.862 0.841 0.982 0.786

1.140 1.148 1.266 1.368 1.279 1.130

0.560 0.963 0.826 0.681 – 0.478

0.34 0.00 0.05 0.17 – 0.50

0.0% 0.0% 0.0% 0.0% – 0.0%

RCT Non-RCT RCT Non-RCT

3 5 2 1

0.455 0.905 0.453 0.872

0.932 0.878 0.931 0.827

1.171 1.122 1.173 1.175

0.460 0.884 0.910 –

1.55 1.16 0.01 –

0.0% 0.0% 0.0% –

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Table 3 Subgroup analysis of adverse events according to certain factors. Subcategory

Nations Japan Others Medications Epirubicin vs. Miriplatin Epirubicin vs. Cisplatin Others Standards CTCAE Other Degrees Grade ≤2 Grade ≥3

Study type

No. of studies

Pooled estimation

Test of heterogeneity

P value

95% Conf. Intervval

P value

Chi-squared

I-squared

RCT Non-RCT RCT Non-RCT

3 1 0 3

0.833 0.782 – 0.327

0.828 0.688 – 0.930

1.164 1.644 – 1.244

0.975 – – 0.047

0.05 – – 6.13

0.0% – – 67.4%

RCT Non-RCT RCT Non-RCT RCT Non-RCT

2 1 1 1 0 2

0.823 0.782 0.984 0.184 – 0.072

0.823 0.688 0.490 0.792 – 0.983

1.168 1.644 2.072 1.063 – 1.500

0.833 – – – – 0.230

0.04 – – – – 1.44

0.0% – – – – 30.7%

RCT Non-RCT RCT Non-RCT

3 2 0 2

0.833 0.218 – 0.944

0.828 0.897 – 0.779

1.164 1.609 – 1.262

0.975 0.375 – 0.084

0.05 0.79 – 2.98

0.0% 0.0% – 66.4%

RCT Non-RCT RCT Non-RCT

3 1 3 1

0.420 0.680 0.101 0.508

0.905 0.711 0.791 0.713

1.270 1.686 1.021 1.182

0.485 – 0.260 –

1.45 – 2.70 –

0.0% – 25.8% –

Ethical approval

pharmacological infusion in TACE depends on many factors. Its feasibility may depend not only on the drug types. Therefore better utilization of the pharmacological efficacy may be more complex than we thought. Although we demonstrated that platinum revealed similar clinical efficacy in TACE comparing with anthracyclines, we must admit that this research contains several shortcomings. First of all, despite a comprehensive and extended search, only 11 studies (4 RCTs and 7 observational studies) were included. We applied stringent inclusion criteria to select appropriate studies and thus might have overlooked some representative papers. Secondly, we applied subgroup analysis for further investigation but the survival rate analysis could not be performed due to insufficient data. Moreover, the Egger's test showed significant bias by analyzing overall survival rate based on RCTs. Thus we redeemed that the effects of platinum and anthracyclines on longterm outcomes still need to be compared in the future. Thirdly, as mentioned above, we required that the included studies must be searched globally to maintain universality and high quality. However, all 11 contains 9 Asian countries (6 from Japan), and this regional limitation may bring potential bias to our final conclusion. In addition, due to the individual differences in patients, some confounding factors may be presented in the original papers. These factors may make our conclusion insufficiently strong. Lastly, quantitative analysis of some parametric data (such as perioperative biological parameters and commercial cost) was not conducted because of inadequate data and we regarded them as subordinate parameters. Despite the existence of several limitations, our results demonstrate the TACE with platinum does not change the therapeutic response, adverse events or survival rate compared with anthracyclines. Thus we concluded that platinum revealed similar clinical efficacy as compared to anthracyclines in TACE. But we still need more studies to make more comprehensive comparisons in the future.

This paper is a meta-analysis and we do not think any Ethical Approval was needed. Sources of funding We do not have any source of funding. Author contribution Mengdie Zhao designed the research; Mengdie Zhao and Ping Xiang performed the research and data collection; Hao Jiang wrote the paper. Conflicts of interest The authors have no conflicts of interest to disclose. Research registration number reviewregistry379. Guarantor Hao Jiang. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx. doi.org/10.1016/j.ijsu.2018.03.049. References

Funding

[1] D.M. Parkin, F. Bray, J. Ferlay, P. Pisani, Global cancer statistics, 2002, CA A Cancer J. Clin. 55 (2005) 74–108. [2] A.P. Venook, C. Papandreou, J. Furuse, L.L. de Guevara, The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective, Oncology 15 (Suppl 4) (2010) 5–13. [3] L. Chang, Y. Wang, J. Zhang, T. Guo, The best strategy for HCC patients at each BCLC stage: a network meta-analysis of observational studies, Oncotarget 8 (2017) 20418–20427.

The work was founded by Natural Science Foundation of Anhui Province (1308085MH164).

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[4] K. Li, H.T. Wang, Y.K. He, T. Guo, New idea for treatment strategies for Barcelona Clinic Liver Cancer stages based on a network meta-analysis, Medicine 96 (2017) e6950. [5] J.F. Geschwind, R. Salem, B.I. Carr, M.C. Soulen, K.G. Thurston, K.A. Goin, M. Van Buskirk, et al., Yttrium-90 microspheres for the treatment of hepatocellular carcinoma, Gastroenterology 127 (2004) S194–S205. [6] C. Cammà, F. Schepis, A. Orlando, M. Albanese, L. Shahied, F. Trevisani, P. Andreone, A. Craxì, et al., Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials, Radiology 224 (1) (2002) 47–54. [7] J.M. Llovet, J. Bruix, Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival, Hepatology 37 (2) (2003) 429–442. [8] J. Bruix, M. Sherman, Management of hepatocellular carcinoma: an update, Hepatology 53 (2011) 1020–1022. [9] European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer, EASLEORTC clinical practice guidelines: management of hepatocellular carcinoma, J. Hepatol. 56 (2012) 908–943. [10] R.J. Morgan Jr., R.D. Alvarez, D.K. Armstrong, R.A. Burger, M. Castells, L.M. Chen, L. Copeland, et al., Ovarian cancer, version 3.2012, J. Natl. Compr. Canc. Netw. 10 (11) (2012) 1339–1349. [11] W.J. Gradishar, B.O. Anderson, R. Balassanian, S.L. Blair, H.J. Burstein, A. Cyr, A.D. Elias, et al., Breast cancer version 2.2015, J. Natl. Compr. Canc. Netw. 13 (4) (2015) 448–475. [12] J.C. Alvarnas, P.A. Brown, P. Aoun, K.K. Ballen, S.K. Barta, U. Borate, M.W. Boyer, et al., Acute lymphoblastic leukemia, version 2.2015, J. Natl. Compr. Canc. Netw. 13 (10) (2015) 1240–1279. [13] A. Rabbani, R.M. Finn, J. Ausió, The anthracycline antibiotics: antitumor drugs that alter chromatin structure, Bioessays 27 (1) (2005) 50–56. [14] H. Nakamura, T. Hashimoto, H. Oi, S. Sawada, Transcatheter oily chemoembolization of hepatocellular carcinoma, Radiology 170 (3 Pt 1) (1989) 783–786. [15] Z.B. Xie, X.B. Wang, Y.C. Peng, S.L. Zhu, L. Ma, B.D. Xiang, W.F. Gong, et al., Systematic review comparing the safety and efficacy of conventional and drugeluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma, Hepatol. Res. 45 (2) (2015) 190–200. [16] D. Moher, A. Liberati, J. Tetzlaff, D.G. Altman, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med. 6 (7) (2009) e1000097. [17] D.F. Stroup, J.A. Berlin, S.C. Morton, I. Olkin, G.D. Williamson, D. Rennie, D. Moher, et al., Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group, J. Am. Med. Assoc. 283 (2000) 2008–2012. [18] J.P.T. Higgins, S. Green, Cochrane handbook for Systematic Reviews of Interventions, The Cochrane Collaboration, 2011 Available: http://handbook. cochrane.org. [19] G.A. Wells, B. Shea, D. O'Connell, J. Peterson, V. Welch, M. Losos, P. Tugwell, The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses, http://wwwohrica/programs/clinical_epidemiology/oxfordasp. [20] M. Egger, G. Davey Smith, M. Schneider, C. Minder, Bias in meta-analysis detected by a simple, graphical test, BMJ 315 (1997) 629–634. [21] M. Ikeda, M. Kudo, H. Aikata, H. Nagamatsu, H. Ishii, O. Yokosuka, T. Torimura, et al., Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial, J. Gastroenterol. 53 (2) (2018) 281–290. [22] K. Kubota, H. Hidaka, T. Nakazawa, Y. Okuwaki, K. Yamane, T. Inoue, H. Uojima, et al., Prospective, randomized, controlled study of the efficacy of transcatheter arterial chemoembolization with miriplatin for hepatocellular carcinoma, Hepatol. Res. 48 (3) (2017) E98–E106. [23] S. Sahara, N. Kawai, M. Sato, H. Minamiguchi, M. Nakai, I. Takasaka, K. Nakata, et al., Prospective comparison of transcatheter arterial chemoembolization with Lipiodol-epirubicin and Lipiodol-cisplatin for treatment of recurrent hepatocellular carcinoma, Jpn. J. Radiol. 28 (5) (2010) 362–368. [24] N. Wang, Y.Z. Lv, A.H. Xu, Y.R. Huang, L. Peng, J.R. Li, Application of lobaplatin in

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33] [34]

[35]

[36]

[37]

[38]

[39]

[40]

158

trans-catheter arterial chemoembolization for primary hepatic carcinoma, Asian Pac. J. Cancer Prev. APJCP 15 (2) (2014) 647–650. M. Arabi, A. BenMousa, K. Bzeizi, F. Garad, I. Ahmed, M. Al-Otaibi, Doxorubicinloaded drug-eluting beads versus conventional transarterial chemoembolization for nonresectable hepatocellular carcinoma, Saudi J. Gastroenterol. 21 (3) (2015) 175–180. T. Aramaki, M. Moriguchi, E. Bekku, K. Asakura, A. Sawada, M. Endo, Comparison of epirubicin hydrochloride and miriplatin hydrate as anticancer agents for transcatheter arterial chemoembolization of hepatocellular carcinoma, Hepatol. Res. 43 (5) (2013) 475–480. T. Handa, Y. Imai, K. Sugawara, T. Chikayama, M. Nakazawa, S. Ando, K. Hamaoka, et al., Transcatheter arterial chemoembolization for hepatocellular carcinoma: comparison of the therapeutic efficacies between miriplatin and epirubicin, Hepatol. Res. 44 (11) (2014) 1072–1080. J.E. Megías Vericat, R. García Marcos, E. López Briz, F. Gómez Muñoz, J. Ramos Ruiz, J.J. Martínez Rodrigo, J.L. Poveda Andrés, Trans-arterial chemoembolization with doxorubicin-eluting particles versus conventional trans-arterial chemoembolization in unresectable hepatocellular carcinoma: a study of effectiveness, safety and costs, Radiologia 57 (6) (2015) 496–504. P. Wiggermann, D. Sieron, C. Brosche, T. Brauer, F. Scheer, I. Platzek, W. Wawrzynek, et al., Transarterial Chemoembolization of Child-A hepatocellular carcinoma: drug-eluting bead TACE (DEB TACE) vs. TACE with cisplatin/lipiodol (cTACE), Med. Sci. Mon. 17 (4) (2011) CR189-95. K. Yamanaka, E. Hatano, M. Narita, K. Taura, K. Yasuchika, T. Nitta, S. Arizono, et al., Comparative study of cisplatin and epirubicin in transcatheter arterial chemoembolization for hepatocellular carcinoma, Hepatol. Res. 41 (4) (2011) 303–309. H. Yodono, K. Matsuo, A. Shinohara, A retrospective comparative study of epirubicin-lipiodol emulsion and cisplatin-lipiodol suspension for use with transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma, Anti Canc. Drugs 22 (3) (2011) 277–282. M. Kudo, S. Kubo, K. Takayasu, M. Sakamoto, M. Tanaka, I. Ikai, J. Furuse, et al., Response evaluation criteria in cancer of the liver (RECICL) proposed by the liver cancer study group of Japan (2009 Revised Version), Hepatol. Res. 40 (7) (2010) 686–692. P. Therasse, E.A. Eisenhauer, J. Verweij, RECIST revisited: a review of validation studies on tumour assessment, Eur. J. Canc. 42 (8) (2006) 1031–1039. A. Facciorusso, R. Licinio, N. Muscatiello, A. Di Leo, M. Barone, Transarterial chemoembolization: evidences from the literature and applications in hepatocellular carcinoma patients, World J. Hepatol. 7 (16) (2015) 2009–2019. J.L. Raoul, B. Sangro, A. Forner, V. Mazzaferro, F. Piscaglia, L. Bolondi, R. Lencioni, Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization, Canc. Treat Rev. 37 (3) (2011) 212–220. R. Sacco, G. Tapete, N. Simonetti, R. Sellitri, V. Natali, S. Melissari, G. Cabibbo, et al., Transarterial chemoembolization for the treatment of hepatocellular carcinoma: a review, J. Hepatocell. Carcinoma 4 (27) (2017) 105–110. S. Kawai, M. Tani, J. Okamura, M. Ogawa, Y. Ohashi, M. Monden, S. Hayashi, et al., Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a comparison of epirubicin and doxorubicin (second cooperative study), The Cooperative Study Group for Liver Cancer Treatment of Japan, Semin. Oncol. 24 (1997) (2 Suppl 6): S6-38- S6–45. A. Facciorusso, M. Di Maso, N. Muscatiello, Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: a meta-analysis, Dig. Liver Dis. 48 (6) (2016) 571–577. K.T. Brown, R.K. Do, M. Gonen, A.M. Covey, G.I. Getrajdman, C.T. Sofocleous, W.R. Jarnagin, et al., Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone, J. Clin. Oncol. 34 (17) (2016) 2046–2053. K. Malagari, M. Pomoni, A. Kelekis, A. Pomoni, S. Dourakis, T. Spyridopoulos, H. Moschouris, et al., Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma, Cardiovasc. Intervent. Radiol. 33 (3) (2010) 541–551.