F1000Research F1000Research 2046-1402 F1000 Research Limited London, UK 10.12688/f1000research.134088.1 Research Article Articles Predictive factors of large liver cell carcinoma tumor response after first conventional transarterial chemoembolization in Indonesia according to the modified response evaluation in solid tumors criteria: a preliminary study

[version 1; peer review: 1 not approved]

 Matondang Sahat Basana Romanti Ezer Conceptualization Funding Acquisition Investigation Methodology Resources Supervision Validation Visualization Writing – Original Draft Preparation Writing – Review & Editing a 1 Lios Liem Arinuryanto Conceptualization Data Curation Formal Analysis Investigation Methodology Project Administration Resources Software Visualization Writing – Original Draft Preparation 1 Hilmy Ibrahim Abubakar Formal Analysis Methodology Project Administration Validation Visualization Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0001-9282-4100 1 2 Hasan Irsan Conceptualization Resources Supervision Writing – Original Draft Preparation Writing – Review & Editing 3 Prihartono Joedo Conceptualization Formal Analysis Methodology Supervision Validation Writing – Review & Editing 4 Department of Radiology, University of Indonesia, Cipto Mangunkusumo National General Hospital, DKI Jakarta, 10430, Indonesia Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo National General Hospital, DKI Jakarta, West Java, Indonesia Department of Internal Medicine, University of Indonesia, Cipto Mangunkusumo National General Hospital, Jakarta DKI, 10430, Indonesia Department of Community Medicine, University of Indonesia, Cipto Mangunkusumo National General Hospital, Jakarta DKI, 10430, Indonesia sahat.basana@ui.ac.id

No competing interests were disclosed.

 15 5 2023 2023 12 500 3 5 2023 Copyright: © 2023 Matondang SBRE et al. 2023 This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Various factors affect the response of large hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE), and the high demand for TACE procedures highlights the need for information and methods on the criteria for patient selection.

Methods: Thirty-six HCC patients who were treated with conventional TACE between January 2014 and January 2020 and had pre- and postoperative imaging data were included in the analysis. The patients were categorized as tumor responders (complete or partial response) or nonresponders (stable or progressive disease) according to the modified response evaluation criteria in solid tumors (mRECIST). Eight predictive factors (Tumor diameter, Tumor amount, tumor vascularity, portal vein invasion, tumor location, presence of tumor capsule, Child–Pugh class, and alpha-fetoprotein (AFP) level) of tumor response were evaluated using multivariate analysis with logistic regression.

Results: Only 42% of patients fell into the category of responders after conventional TACE. None of the Child–Pugh class B patients showed a tumor response. A multivariate analysis of the Child–Pugh class A patient group showed that a lesion diameter of 5–10 cm (OR: 8.78, 95% CI: 1.73–44.55; P = 0.009) are an independent predictor of tumor response after the first TACE procedure.

Conclusions: A tumor diameter of 5–10 cm could be use as a predictor of tumor response after the first conventional TACE in Child–Pugh A patients, further researches are needed to confirm this finding.

 Hepatocellular carcinoma HCC TACE Transarterial Chemoembolization Predictive factors mRECIST Modified response evaluation in solid tumors criteria Radiology The author(s) declared that no grants were involved in supporting this work. Introduction

According to International Agency for Research on Cancer data, hepatocellular carcinoma (HCC) was the fifth most common cancer and the third most common cause of death from cancer globally in 2020. 1 In Indonesia, there were 21,392 new cases of liver cancer in 2020, with a mortality rate of 7.7 deaths per 100,000 people. 2

HCC treatment options can be divided into curative and non-curative. Curative therapy is indicated for early stages and includes surgical resection, liver transplantation, and radiofrequency ablation. 3 Non-curative (palliative) treatment aims to prolong survival by slowing tumor progression. Transarterial chemoembolization (TACE) is the most frequently used palliative procedure. 1 , 3 , 4 The median survival rate of HCC patients receiving TACE ranges from 13.7 to 17 months. 3 , 5 A systematic review of randomized clinical trials found that TACE provided better two-year survival than supportive therapy. 6

Tumor response can be used as a measure of the efficacy of therapy and has been identified as an independent predictor of survival. 6 The modified response evaluation criteria in solid tumors (mRECIST) system is used to determine the response to targeted tumor lesions, which is classified as complete response, partial response, progressive disease, and stable disease. 7

Various studies have attempted to identify the predictive factors of tumor response after TACE. Hong et al. found that a tumor size of <4 cm, fewer than five tumors, hypervascular tumors, and the absence of portal vein invasion predicted a post-TACE tumor response. 5 Mickey et al. reported that Child–Pugh class A patients responded better to tumors located in the right lobe and medial segment after TACE. 8 Jeong et al. found that a tumor size of <5 cm and a single tumor were predictors of a complete response. 9 Banangkoon et al. found that fewer than two sessions of selective TACE, a serum alpha-fetoprotein (AFP) level of <100 ng/mL, a cumulative tumor diameter of <30 mm, and unilobar involvement were predictors of a complete response. 10 Wu et al. reported that the presence of a tumor capsule was a significant prognostic factor in HCCs with a tumor size of >5 cm. 11

Although several studies have assessed the determinants of tumor response, few such studies have been conducted in Indonesia. Loho et al. found that the average tumor diameter of HCC patients in Indonesia was 10.9 ± 4.9 cm and that more than 94% of patients had a tumor with diameter of >5 cm. 12 The large tumor size of patients in Indonesia, along with long patient list for TACE procedures, and the large number of patients lost due to death made it difficult to achieve therapeutic targets. Thus, there is a need for research in determining factors to be considered in predicting tumor response to assist and hasten the prioritizing process for patients with better chance for response.

 Methods Study design

This retrospective observational study used secondary data from HCC patients receiving conventional TACE in the radiology department of a tertiary hospital in Jakarta from January 2014 to January 2020. The inclusion criteria were HCC patients with target lesions measuring >5 cm who received conventional TACE (lipiodol and doxorubicin emulsion and embolization with a gelatin sponge) and had multiphase abdominal CT/MRI examinations within two months before the procedure and one to three months after the procedure. Patients with a previous history of systemic or locoregional therapy were excluded.

In this preliminary study, we evaluated eight factors, each divided into two categories: tumor diameter (5–10 cm or >10 cm), number of tumors (single or multiple), tumor vascularity (hypovascular or hypervascular), portal vein invasion (present or absent), tumor location (right/medial or left/bilateral), tumor capsule (present or absent), Child–Pugh class (A or B/C), and AFP level (<400 ng/mL or ≥400 ng/mL). Patients were divided into two groups according to tumor response status: responders (complete or partial response) and nonresponders (stable or progressive disease). Our aim was to determine whether these factors can be used as predictors of tumor response and assist in prioritizing patients for treatment. Due to the high rate of loss to follow-up, we evaluated tumor responses only after the first TACE.

 Data collection

A total of 41 patients were identified in the hospital’s registry. Five patients were excluded due to previous HCC therapy (either surgical or interventional). Four of the remaining 36 patients' laboratory data were either incomplete or missing and thus their Child–Pugh class cannot be determined; however, one of those four patients had their Child–Pugh class in their diagnosis record, therefore they were still included in the Child–Pugh class analysis. The other three patients were also included in the tumor characteristics analysis because they had complete radiological data. ( Figure 1) The patients’ tumor characteristics and responses were analyzed using a picture archiving and communication system (PACS). Demographic (sex and age), laboratory, clinical (etiology [hepatitis B, C, or neither] and cirrhosis status), and Child–Pugh class data were collected from the patients’ medical records. To eliminate bias, tumor analysis was performed independently by two radiologists blinded to the patients’ identities.

Patient eligibility and categorization flowchart. Variables

Tumor characteristics (diameter, number, location, vascularization, portal vein invasion, and presence of capsules) were assessed by the examining radiologist using PACS. The number of tumors and their locations were determined by the examining radiologist by examining either CT or multiphase MRI scans using PACS. The baseline tumor diameter was measured using the ruler function of PACS. In cases of more than one lesion, the five largest lesions’ diameters at most were added up. The post-TACE diameter measurements were based on viable lesions with the largest diameters. The presence of a tumor capsule was determined by the radiologist on CT or multiphase MRI as a thin, hyperattenuated or hyperintense layer in the delayed phase of the scan and as either a hyper- or hypoattenuated layer in the portal vein phase. Portal vein invasion, also measured in the portal vein phase, was defined as the obliteration of normal portal vein structure and/or intraluminal portal vein thrombosis.

Tumor response was categorized by comparing pre- and postoperative imaging using the mRECIST. Patients with complete or partial responses were categorized as responders (cases), while patients with stable or progressive disease were categorized as nonresponders (controls).

 Data analysis

All data were analyzed using International Business Machines Corporation Statistical Package for the Social Sciences (IBM SPSS) Statistics version 20. Relationships between two categorical variables were assessed using the chi-squared test or Fisher’s exact test if the total sample size was too small. Relationships between categorical and numerical variables were assessed using the independent t-test if the distribution was normal or the Mann–Whitney U test if the distribution was not normal. Predictive factors with P-values of <0.20 in bivariate analysis were included in multivariate analysis using logistic regression with the Enter approach to construct a prognostic model with an alpha significance limit of 5%. Bilirubin and albumin levels were not analyzed as predictive factors but as components of the Child–Pugh classification system, which was assessed as a predictive factor. AFP was evaluated as an independent predictor.

 Results Patients’ demographic, clinical, and laboratory data

The patients’ mean age was 59.7 ± 10.8 years. Most (72%) patients were male. Hepatitis B infection was found in almost two-thirds of the patients, whereas cirrhosis was found in only 10 patients. A total of 28 out of 33 patients (85%) were Child–Pugh class A, while the rest were class B. None were class C. The AFP levels of 64% of the patients were below 400 ng/mL. ( Table 1) A tumor diameter of >10 cm was found in 22 patients, while a single tumor/lesion was present in 24 patients. Most (78%) patients had tumors in the right lobe or medial segment. Hypervascular tumors were found in 27 patients. Portal vein invasion was found in only nine patients. Tumor capsules were found in 15 patients (42%)( Table 2).

Patients’ demographic characteristics and laboratory parameters.
Demographic characteristics and laboratory parameters n (%) Mean ±SD/median (range)
Sex
Male 26 (72)
Female 10 (28)
Age (years) 59.7 ± 10.8
Etiology
Hepatitis B 21 (64)
Hepatitis C 6 (18)
Other 6 (18)
Cirrhosis
Yes 10 (28)
No 26 (72)
Albumin 3.79 ± 0.57
Bilirubin 0.78 (0.2–4.86)
Prothrombin time (PT) 11.23 ± 2.23
Alpha-fetoprotein (AFP) 70 (1.6–400,000)
Child–Pugh class
A 28 (85)
B 5 (15)
C 0
Alpha-fetoprotein (AFP) level
<400 21 (64)
≥400 11 (36)
Patients’ tumor characteristics.
Tumor characteristic n (%)
Largest diameter
5–10 cm 14 (39)
>10 cm 22 (61)
Tumor number
Single 24 (67)
Multiple 12 (33)
Lesion location
Right/medial 28 (78)
Left/bilateral 8 (22)
Vascularization
Hypervascular 27 (75)
Hypovascular 9 (25)
Portal vein invasion
Yes 9 (25)
No 27 (75)
Tumor capsule
Yes 15 (42)
No 21 (58)
Bivariate and multivariate analyses

The bivariate analysis showed that a tumor diameter of 5–10 cm (OR: 8.5, 95% CI: 1.88–36.30; P = 0.004) could have an association with tumor response and therefore will be included in multivariate analysis. The presence of a tumor capsule (OR: 3.75, 95% CI: 0.9–14.81; P = 0.059) and Child–Pugh class A (OR: 9.58, 95% CI: 1.0–92.09; P = 0.131) were also included in the multivariate because their P value are <0.20. Conversely, the number and location of lesions, vascularization, portal vein invasion, and AFP levels did not significantly affect the response ( Table 3).

Bivariate analyses of predictive factors of tumor response.
Variable Univariate analysis
Tumor response status P OR 95% CI
Response No response
Sex *
Male 12 14 0.458 2.0 0.43–9.36
Female 3 7
Etiology †
Hepatitis B 9 12 0.427 3.75 0.41–34.22
Hepatitis C 2 4 1.00 2.5 0.17–36.97
Other 1 5
Cirrhosis †
Yes 4 6 >0.999 0.91 0.21–4.01
No 11 15
Tumor number †
Single 9 15 0.473 0.60 0.15–2.42
Multiple 6 6
Lesion location *
Right/medial 13 16 0.674 2.08 0.35–11.97
Left/bilateral 2 5
Lesion diameter †
5–10 cm 10 4 0.004 8.50 1.99–36.30
>10 cm 5 17
Lesion vascularization *
Hypervascular 13 14 0.252 3.25 0.60–17.63
Hypovascular 2 7
Portal vein invasion *
Yes 4 5 >0.999 1.16 0.25–5.33
No 11 16
Tumor capsule †
Yes 9 6 0.059 3.75 0.95–14.81
No 6 15
Alpha-fetoprotein level *
<400 9 12 0.456 2.00 0.42–9.62
≥400 3 8
Child–Pugh class *
A 13 15 0.131 9.58 1.00–92.09
B or C 0 5

Fisher’s exact test.

Chi square test.

The multivariate analysis considered predictive factors only for Child–Pugh class A patients because none of the Child–Pugh class B patients were tumor responders. A larger tumor diameter of 5–10 cm (OR: 8.78, 95% CI: 1.73–44.55; P = 0.009) was found to be an independent predictor of tumor response after the first TACE procedure ( Table 4).

Multivariate analyses of predictive factors of tumor response.
Variable Tumor response status Multivariate analysis
Response No response B P OR 95% CI
Lesion diameter
5–10 cm 10 4 2.17 0.009 8.78 1.73–44.55
>10 cm 5 17
Tumor capsule
Yes 9 6 1.37 0.096 3.93 0.78–19.72
No 6 15
Discussion

This preliminary study aimed to find the factors that could be used as a predictor for tumor response, we evaluated eight factors that could be associated with tumor response and found a tumor diameter of 5-10 cm could be used as predictor.

In this study, we found that there were five Child–Pugh class B patients, none of whom showed a tumor response. While Miki et al. found that Child–Pugh class A and a tumor in the right lobe or medial segment were associated with a higher probability of complete tumor response. They also found that there were some patients with Child–Pugh class B that showed a response. 8 Our study found that no patients from the Child–Pugh class B showed a tumor response. There are several factors that could explain this: first, only 15% out of 33 patients with Child–Pugh data were class B. Second, all of them had a tumor diameter >10 cm. The small sample size in this category and the large size of their tumor may explain why they showed no response.

Tumors with a diameter of 5–10 cm were associated with a higher probability of tumor response. This suggests that tumor diameter is an independent predictor of tumor response. This finding conflicts with previous studies reporting that a small tumor diameter (<5 cm) is a predictor of a complete response. 5 , 9 , 11 But the fact that this study included no patients with a small tumor diameter (<5 cm) may explain the conflicting results.

The presence of tumors in the right lobe or medial segment was not shown to be an independent predictor in this study. Of the 29 patients with right/medial lobe tumors, 16 were nonresponders, and 14 had a tumor diameter of >10 cm, with an average of 15.9 cm. This finding differs from previously stated study by Miki et al. that showed an association between tumor in right lobe or medial segment and tumor response. The large diameter of the tumor in the right lobe or medial segment in this study might explain why tumors in the right lobe or medial segment did not predict a tumor response. Likewise, the number of tumors was not an independent predictor. Conversely, Jeong et al. and Hong et al. reported that a single tumor with a small diameter (<4 cm) predicted a complete response. 5 , 13 In this study, all tumors were >5 cm in diameter. The difference in target sample’s tumor size might explain why the number of tumors was not a predictive factor.

Banangkoon et al. found that an AFP level of <100 ng/mL was one of the factors that predicted a complete tumor response, the other being a tumor size of <30 mm. 10 In this study, 21 patients had AFP levels of <400 ng/mL. Twelve of them were nonresponders, and eight had a tumor diameter of >10 cm, with an average of 15 cm. The combination of a large tumor diameter and an AFP level of <400 ng/mL might explain why these patients showed no tumor response.

In this study, the presence or absence of portal vein invasion and hypervascular tumors did not predict a tumor response. Conversely, Hong et al. reported that hypervascular tumors and the absence of portal vein invasion were predictors of tumor response. 5 On the other hand, Wu et al. found that in tumors larger than 5 cm, vascular invasion did not predict a good tumor response; only the presence of a tumor capsule was associated with a favorable prognosis. 11 In this study, 16 patients without portal vein invasion were nonresponders, 13 of whom had a tumor diameter of >10 cm, with an average of 17 cm. A total of 27 patients had hypervascular tumors. Fourteen of them were nonresponders, and 10 had a tumor diameter of >10 cm, with an average of 16.9 cm. The large tumor diameter may explain the lack of tumor response even in the absence of portal vein invasion and hypervascular tumors.

In this study, we found that the presence of a tumor capsule was not an independent predictor of tumor response. This conflicts with the findings of Wu et al., 11 who found that in tumors measuring >5 cm, only the presence of a tumor capsule was a favorable prognostic factor. The difference in finding could be due to the difference in sample size and that Wu et al. did not specifically examine for response after first TACE procedure, but after hepatectomy instead.

This research had several limitations. First, the number of subjects analyzed in this study was relatively small, therefore further studies are needed to confirm the validity of the findings of this study. Second, because it was a retrospective study, some laboratory data (albumin, bilirubin, prothrombin time, and AFP) could not be obtained, thus some patient’s Child–Pugh class could not be determined. Third, because no Child–Pugh class B patients showed a tumor response, the Child–Pugh class was excluded from the multivariate analysis.

In conclusion, in this study, a tumor diameter of 5–10 cm was an independent predictor of tumor response in Child–Pugh class A patients after the first conventional TACE procedure. Therefore, Child–Pugh class A patients with a tumor size of 5–10 cm could be prioritized for conventional TACE. We acknowledge that due to the small sample size analyzed in this study, further studies with larger sample sizes and multicenter designs (provided that they have uniform procedure protocols) should be conducted to confirm the results of this study.

Ethical considerations

This study was approved by the ethics committee of the hospital (No. KET-437/UN2.F1/ETIK/PPM.00.02/2020). Due to the study’s retrospective nature, the requirement for written informed consent was waived.

 Data availability Underlying data

Zenodo: Predictive factors of large liver cell carcinoma tumor response after first conventional transarterial chemoembolization in Indonesia according to the modified response evaluation in solid tumors criteria: a preliminary study (supplemental data), https://doi.org/10.5281/zenodo.7834809. 14

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

 Acknowledgments

We acknowledge the help of Eghar Anugrapaksi, M.D. in his role to interpret and confirm the statistical analysis of this study.

 References International Agency for Research on Cancer: All Cancers Source GLOBOCAN 2020. Int Agency Res Cancer;2021. Reference Source International Agency for Research on Cancer: Indonesia Source GLOBOCAN 2020. Int Agency Res Cancer;2021. Reference Source White JA Gray SH Li P : Current guidelines for chemoembolization for hepatocellular carcinoma: room for improvement? Hepatol Commun. 2017;1(4):338–346. 29404463 10.1002/hep4.1046 PMC5721390 Kobayashi T Kawai H Nakano O : Rapidly declining skeletal muscle mass predicts poor prognosis of hepatocellular carcinoma treated with transcatheter intra-arterial therapies. BMC Cancer. 2018;18(1):1–9. 10.1186/s12885-018-4673-2 Hu HT Kim JH Lee LS : Chemoembolization for hepatocellular carcinoma: multivariate analysis of predicting factors for tumor response and survival in a 362-patient cohort. J. Vasc. Interv. Radiol. 2011;22(7):917–923. 10.1016/j.jvir.2011.03.005 Llovet JM Bruix J : Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology. 2003;37(2):429–442. 12540794 10.1053/jhep.2003.50047 Lencioni R Llovet JM : Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 2010;30(1):052–060. 10.1055/s-0030-1247132 Miki I Murata S Uchiyama F : Evaluation of the relationship between hepatocellular carcinoma location and transarterial chemoembolization efficacy. World J. Gastroenterol. 2017;23(35):6437–6447. 29085193 10.3748/wjg.v23.i35.6437 PMC5643269 Park HJ Kim JH Choi SY : Prediction of therapeutic response of hepatocellular carcinoma to transcatheter arterial chemoembolization based on pretherapeutic dynamic CT and textural findings. Am. J. Roentgenol. 2017;209(4):W211–W220. 28813195 10.2214/AJR.16.17398 Bannangkoon K Hongsakul K Tubtawee T : Rate and predictive factors for sustained complete response after selective transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma. Asian Pac. J. Cancer Prev. 2018;19(12):3545–3550. 30583681 10.31557/APJCP.2018.19.12.3545 PMC6428524 Wu TH Yu MC Chen TC : Encapsulation is a significant prognostic factor for better outcome in large hepatocellular carcinoma. J. Surg. Oncol. 2012;105(1):85–90. 22161900 10.1002/jso.22060 Loho IM Hasan I Rinaldi C : Hepatocellular carcinoma in a tertiary referral hospital in Indonesia: Lack of improvement of one-year survival rates between 1998-1999 and 2013-2014. Asian Pac. J. Cancer Prev. 2016;17(4):2165–2170. 10.7314/APJCP.2016.17.4.2165 Jeong SO Kim EB Jeong SW : Predictive factors for complete response and recurrence after transarterial chemoembolization in hepatocellular carcinoma. Gut Liver. 2017;11(3):409–416. 28208001 10.5009/gnl16001 PMC5417784 Matondang SBRE : Predictive factors of large liver cell carcinoma tumor response after first conventional transarterial chemoembolization in Indonesia according to the modified response evaluation in solid tumors criteria: a preliminary study (supplemental data).[Data set]. Zenodo. 2023. 10.5281/zenodo.7834809 10.5256/f1000research.147114.r269141 Reviewer response for version 1 Miyayama Shiro 1 Referee https://orcid.org/0000-0001-6119-5874 Department of Diagnostic Radiology, Fukuiken Saiseikai Hospital, Fukui, Japan

Competing interests: No competing interests were disclosed.

 13 9 2024 Copyright: © 2024 Miyayama S 2024 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recommendation reject

1. This study included many HCCs >10 cm. I think that it is very difficult to embolize HCCs >10 cm by a single cTACE session, because they are usually supplied by many arterial branches including extrahepatic arteries. I speculate that almost HCCs >10 cm in the present study might not be successfully embolized in a single TACE session. So, evaluation of technical success of cTACE (embolization of the entire tumor) is necessary before the discussion of the prognostic factor of tumor response. The authors should describe how they evaluated the technical success of cTACE in the present study.

2. To treat large HCCs with cTACE, some special techniques, such as bland embolization followed by cTACE (Hidaka T, et al.2021 [Ref 1]), drug-eluting bead TACE followed by cTACE (Morishita A, et al.2021 [Ref 2]), and stepwise superselective cTACE (Miyayama S, et al.2010 [Ref 3], Miyayama S.et.al., 2019 [Ref 4]) have been reported. Please cite these papers and discuss the TACE techniques to embolize a large tumor safely and effectively.

3. The authors compared the predictors of tumor response in the present study among several papers; however, some reported significant predictors were found in the study of cTACE for small HCCs. Therefore, the comparisons might not be meaningful because the tumor backgrounds in such reports might be extremely different from the present study. I speculate that the most significant predictor of tumor response in the present study might be “embolization of the entire tumor”.

4. If many tumors were not successfully embolized in a single cTACE session in this cohort, the contents and discussion points of this manuscript should be changed to “difficulty in the whole tumor embolization of large HCCs in a single cTACE session.”

5. The details of the cTACE procedure are unclear. Please add the details of cTACE techniques, for example, the use of a microcatheter and CT/cone-beam CT, a total dose of Lipiodol emulsions (water-in-oil or oil-in-water?) in a single session, the size of particle embolus, and additional cTACE through extrahepatic arteries. The endpoint of cTACE should also be clarified.

6. cTACE for large HCCs might also cause severe complications. Please describe the complications in each patient.

Is the work clearly and accurately presented and does it cite the current literature?

No

If applicable, is the statistical analysis and its interpretation appropriate?

Not applicable

Are all the source data underlying the results available to ensure full reproducibility?

No

Is the study design appropriate and is the work technically sound?

No

Are the conclusions drawn adequately supported by the results?

Partly

Are sufficient details of methods and analysis provided to allow replication by others?

No

Reviewer Expertise:

TACE for hepatocellular carcinoma

I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

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