Long-term survival outcomes of drug-eluting bead transarterial chemoembolization in patients with hepatocellular carcinoma in Vietnam

doi:10.21203/rs.3.rs-2744838/v1

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Long-term survival outcomes of drug-eluting bead transarterial chemoembolization in patients with hepatocellular carcinoma in Vietnam

https://doi.org/10.21203/rs.3.rs-2744838/v1

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Aim

To evaluate the efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) and determined prognostic factors affecting patients with HCC.

Methods

A total of 477 Vietnamese patients diagnosed with HCC underwent DEB-TACE. Patient survival was assessed using the Kaplan–Meier method, and prognostic factors affecting survival were assessed using log-rank tests and Cox proportional hazards regression.

Results

Among the 477 patients (437 males, mean age 61.1 ± 11.7 years) who underwent DEB-TACE, the median clinical follow-up was 25.3 (1–63) months. Treated response according to the Modified RECIST in patients followed up beyond 6 months included a complete response (CR) in 41 patients (8.7%), partial response (PR) in 352 (74.9%), stable disease (SD) and progressive disease (PD) in 77 (16.1%). The median overall survival (OS) was 53 ± 1.1 months. Factors associated with longer OS included ECOG ≤ 1, Child-Pugh A, BCLC stage A/B, ALBI grade I, and tumor response (CR/PR). In multivariate analysis, Child-Pugh A and objective tumor response (CR/PR) were predictors of longer OS.

Conclusion

DEB-TACE was an effective treatment for HCC. Child-Pugh A before TACE and tumor response (CR/PR) were positive prognostic factors.

Biological sciences/Cancer

Health sciences/Diseases

Health sciences/Oncology

Hepatocellular carcinoma

Drug-eluting bead transarterial chemoembolization

Long-term survival

Tumor response

In Asia, liver cancer has been on top of general cancer incidence and caused major deaths related to cancer diseases, which counted 72,5% of all liver cancer patients in the world [1]. Approximately 80% of primary neoplasm of the liver cancer cases are identified as hepatocellular carcinoma (HCC) [2]. Hepatitis B virus and C virus are parts of the main pathogen causing HCC in Asia, particularly in Vietnam. Therefore, HCC screening tests should be applied for chronic hepatitis and liver cirrhosis patients every 2 years, who may get early diagnoses and efficacy treatment [3]. In clinical practice, the Barcelona Clinic Liver Cancer (BCLC) staging system is the most widely used classification system for HCC [4]. This classification helps to evaluate prognostic factors including tumor burden, liver function, overall health status, and stratifies survival according to clinically applicable stages [5]. Recently, the Up-to-seven criteria, which the total number of tumors and the largest tumor size (measured in cm) does not exceed 7, was introduced among HCC BCLC stage B [6]. Up to now, strategy of treatment of HCC stage B has changed quickly, however there is currently no specific optimal treatment method [7].

Transarterial chemoembolization (TACE) is the most widely used treatment method for intermediate-stage hepatocellular carcinoma (HCC) that is not suitable for curative treatment, and it is the first choice for patients in the BCLC stage B subgroup [4, 7]. TACE includes traditional lipiodol-based TACE and drug-eluting bead TACE (DEB-TACE). Both TACE techniques have been shown to be effective and safe, providing survival benefits for patients in randomized controlled trials and meta-analyses [8, 9]. In Vietnam, DEB-TACE has utilized since 2014. In this study, we evaluated the actual treatment results of Vietnamese HCC patients using DEB-TACE and following up for 5 years at 108 Military Central Hospital. Additionally, we assessed prognostic factors affecting on these results.

For five years, among 1690 inpatients with HCC, there were 674 patients received DEB-TACE treatment, including both first-time and non-first-time diagnoses. Among them, 477 patients were taken their first treatment with DEB-TACE.

Patient characteristics at the baseline

Total 477 HCC patients were treated firstly with DEB-TACE from January 2017 to April 2022. The average age of patients was 61.1 ± 11.7 years (ranging from 32 to 89 years) while males were predominant (91.6%). Moreover, a majority of patients had hepatitis B (84.1%) and ECOG score at 0 or 1 (92.3%). In addition, over half of the patients had cirrhosis (59.7%), however most patients had compensated liver function, with 80.3% of Child-Pugh A, 89.4% of the ALBI grade I or grade II.

Patients with BCLC stages A and B (77.1%) were more than three times higher than those stages C and D. The average tumor size was 7.1 ± 3.9 cm, with tumors < 7 cm accounting for more than half (58%). The proportion of patients with AFP > 200 ng/ml was 51.5% (Table 1).

The treatment response

Out of 477 patients, 470 were monitored for tumor response at 3 and 6 months after treatment. After the first treatment, 85.9% patients had tumor response, following 5.9% of those had stable diseases. At 6 months, the complete response (CR) rate was 8.7% (41 patients), partial response (PR) rate was 74.9% (352 patients), stable disease (SD) rate was 9.1% (43 patients), and progression disease (PD) rate was 7.2% (34 patients) (Table 2).

The median follow-up time after the intervention was 25.3 months (1–63 months), with 22 patients lost to follow-up. Additionally, 77 patients died because of progression of tumors. The overall median survival time was 53 ± 1.1 months (95%CI: 51.1–55.4). The overall survival rates at 1 year, 3 years, and 5 years were 82%, 78%, and 69%, respectively (Fig. 1).

Factors affecting

Analysis of factors influencing survival time is shown in Table 3

In univariate analysis, the overall survival time was higher in the group with ECOG total score ≤ 1 (55.1 ± 1.1 months) compared to ECOG ≥ 2 (34.9 ± 4.4 months) (p < 0.001); In addition, the longer suvival recorded in patients with ALBI grade I (58.1 ± 1.5 months) compared to ALBI grade II,III (49.9 ± 1.5 months) (p = 0.002); in Child-Pugh A liver function (56.9 ± 1 months) compared to Child-Pugh B/C (40.2 ± 1.1 months) (p < 0.001); in BCLC stage A/B (55.2 ± 1.1 months) compared to BCLC stage C/D (46.9 ± 2.6 months) (p = 0.001); in tumor response (CR/PR) (58.7 ± 0.9 months) compared to stable/progressive disease (21.6 ± 2.9 months) (p < 0.001).

In multivariate analysis, the factors influencing the survival time were: liver function (Child-Pugh A and Child-Pugh B/C) (HR 0.37, df = 1, 95% CI 0.19–0.73, p = 0.004). Tumor response (CR/PR) compared to stable/progressive disease (HR = 0.04, df = 1, 95% CI 0.02–0.08, p < 0.001).

Currently, transarterial chemoembolization (TACE) is recommended for treating intermediate stage hepatocellular carcinoma (HCC) patients with tumors that cannot be surgically removed or treated by percutaneous ablation. TACE may also be selectively indicated in HCC patients with vascular invasion. Additionally, this is a method of treatment for downstaging or bridging therapy for liver transplant candidates while waiting for transplantation [10].

TACE can be performed using two techniques: conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE). The efficacy of tumor destruction and survival between the two techniques is equivalent. However, the risk of vascular and biliary injury as well as post-intervention syndrome of DEB-TACE is lower than that of cTACE, especially for larger tumors. DEB-TACE is made of drug-loaded microspheres that not only cause tumor vascular occlusion but also gradually release the drug to prolong tumor cell damage and decrease the systemic circulation of the drug. In many clinical situations, TACE is more widely indicated in Asian countries based on different staging systems.

In our study, which involved 477 patients, DEB-TACE was applied for most BCLC stages. Patients with BCLC C and BCLC D stages were usually indicated for prophylactic purposes to prevent tumor rupture due to a large tumor size or bridging to liver transplantation. The tumor response rate at 3 months and 6 months in this study was 85.9% and 83.6%, respectively. These results are higher than some other studies worldwide. Li et al. [11] analyzed 172 HCC patients treated with DEB-TACE, and the response rate after 6 months was 63.2%. Other studies reported response rates after 6 months ranging from 51.6–73.2% [12]. The difference in results may be due to the patient selection criteria of each study, the multidisciplinary and multimodal approach in the treatment of HCC.

Analyzing overall survival in 477 patients, the mean overall survival time was 53 ± 1.1 months (95%CI: 51.1–55.4). The overall survival rates at 1 year, 3 years, and 5 years were 89%, 78%, and 69%, respectively. A study conducted on 200 UBTG patients treated with DEB-TACE for downstaging before transplantation or bridging achieved a median overall survival of 3.15 years, with overall survival rates at 1 year, 3 years, and 5 years being 95%, 88.2%, and 73.5%, and 82.8%, 76.5%, and 72.3%, respectively [13]. Comparing the results with some other authors is shown in Table 4 [14–17]

Therefore, there are differences in survival benefits among studies, so it is necessary to identify prognostic factors that can predict the survival of patients treated with DEB-TACE. In our study, patients with good ECOG performance status scores of 0–1 and ALBI grade I were associated with better survival outcomes. Recently, studies have used the ALBI grade to evaluate liver function, helping clinicians make treatment decisions. This index is also an independent prognostic factor for overall survival and liver failure after intervention in patients treated with TACE, embolization, external beam radiation therapy, and systemic therapy [18]. Child-Pugh liver function, BCLC stage, and tumor response are also independent prognostic factors that affect OS in patients. These results are consistent with other studies worldwide [19, 20]. In multivariate analysis, Child-Pugh classification and tumor response were two independent prognostic factors affecting overall survival of patients. These are two factors that have been noted in many different studies. Author Dhanasekaran and colleagues [19] studied 50 patients with UBTG who were no longer candidates for surgical TACE treatment, and Child-Pugh A classification was an independent prognostic factor for prolonged overall survival of patients with p = 0.002 (HR 6.1 CI: 1.7–22.3), similar to the study by Lee and colleagues [12] with p = 0.03.

Comparing with another study of ours using selective internal radiation therapy with yttrium-90 (SIRT Y⁹⁰) [21], it seems that the first-time treatment of liver cancer with DEB-TACE leads to better tumor response and longer overall survival (89.5% vs 59.8% after 3 months of the treatment, and 53 months vs 23.9 months of overall survival, respectively). The significant difference in results between our two studies is mainly due to the differences in patient populations. This study had 77.1% of patients in the early and intermediate stages of the disease, while the previous study had 60.8% of patients in the advanced stage. However, both studies achieved comparable results to other reports around the world, and achieved good efficacy in treating unresectable HCC.

This study still has many limitations, being a retrospective study without a control group to compare treatment outcomes. After DEB-TACE treatment, patients may receive other combined methods such as surgery, liver transplantation, radiofrequency ablation, targeted therapy, which may affect the results.

In conclusion, through a retrospective analysis of a large sample size of unresectable HCC patients treated firstly with DEB-TACE, our study results demonstrates that DEB-TACE is effective and provides long-term survival benefits for patients. In multivariate analysis, good liver function of Child-Pugh class A and response of the tumor to treatment were independent prognostic factors for overall survival.

Patients

Four hundred and seventy-seven Vietnamese HCC patients were received DEB-TACE treatment. All patients enrolled 108 Military Central Hospital from 01/2017 to 04/2022.

* Inclusion criteria for patients:

- To confirm as HCC patients based on the diagnosis and treatment guidelines of the Vietnamese Ministry of Health in 2020 [22]

- To catalogue as unresectable HCC at the diagnosis

- To receive their first treatment with DEB-TACE

* Exclusion criteria:

Another cancer patients treated with DEB-TACE
Patients were not received their first treatment as DEB-TACE

Ethics statement

The study protocol was performed according to the principles of the 1975 Declaration of Helsinki and the study was approved by the Institutional Review Board of 108 Military Central Hospital (No;3761/HDDD). Informed consent was obtained from all individual participants after detailed explanation of the treatment. All patients were discussed by the hospital's multidisciplinary team and approved for DEB-TACE treatment by the hospital directorate.

Method:

Retrospective study of medical records stored in the archives and on the VIMES software (electronic medical records) of patients diagnosed with HCC and treated for the first time with DEB-TACE from January 2017 to April 2022.
Study content: Collect variables including age, gender, medical history, risk factors, clinical symptoms, imaging findings including Child-Pugh liver function, albumin-bilirubin (ALBI) score, kidney function, BCLC stage, AFP before and after the first intervention at 3 months and 6 months; follow-up for overall survival until the end of the study or patient death.
The main outcome of the study was overall survival (OS), tumor response after DEB-TACE according to mRECIST [23], and prognostic factors affecting overall survival.

Statistical analysis:

Descriptive statistics for nominal, ordinal, and continuous variables, including frequency, median, and average, were used as appropriate. Proportions were compared using chi-squared tests with continuity correction or Fisher’s exact tests, as appropriate. The Kaplan-Meier test was used to assess the overall survival time. The log-rank tests and Cox proportional hazards regression models were applied to evaluate prognostic factors affecting on the patients’ survival. To assess the variation in each liver function test over the previous follow-up, we used one-way analysis of variance. Statistical analyses were performed using SPSS version 22 (SPSS Statistics, IBM, Armonk, NY, USA). Significance was set at P<0.05.

Acknowledgements

We thank all patients and healthy individuals for their participation.

Conflict of interests

All authors have no conflicts of interest to declare.

Funding

No funding

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to the privacy policy of the Vietnam military hospital, but are available from the corresponding author on reasonable request.

Authors’ contributions

MTB, NVT, and NTT have full access to all data in the study and take responsibility for data integrity and analysis accuracy. Study concept and design: MTB, NVT. Acquisition of data: DTG, NVM, TTAT, NAT, NTHT. Analysis and interpretation of data: MTB. Validation: MHB, NTT. Drafting of the manuscript: TNV. Statistical analysis: TNV. Writing – review & editing: MTB. All authors read and approved the final version of the manuscript.

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Table 1: Baseline characteristics. AFP, alpha-fetoprotein, ALBI, albumin-Bilirubin grade, BCLC, Barcelona Clinic Liver Cancer staging system

Variables N=477 (%)
Age (years)	< 65	256 (56.4)
	≥65	198 (43.6)
Sex	Male	437 (91.6)
	Female	40 (8.4)
Etiology	Hepatitis B	401 (84.1)
	Hepatitis C	31 (6.5)
	Alcohol	24 (5)
	Cirrhosis	285 (59.7)
Performance status	0	307 (64.4)
	1	133 (27.9)
	2	12 (12.4)
	3	28 (5.9)
	4	3 (0.6)
Index lesion size (cm)	≤7	257(58)
	> 7	186 (42)
AFP	<200	196 (48.5)
	≥200	208 (51.5)
ALBI class	Grade I	160 (35.2)
	Grade II	246 (54.2)
	Grade III	48 (10.6)
Child-Pugh class	A	383 (80.3)
	B	75 (15.7)
	C	19 (4)
BCLC stage	A	104 (21.8)
	B	264 (55.3)
	C	85 (17.8)
	D	24 (5)

Table 2: Tumor response based on mRECIST guideline. mRECIST, Response Evaluation Criteria In Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

Time point	Number of patients (n=477)	Tumor response, n (%)
Time point	Number of patients (n=477)	CR	PR	SD	PD
Baseline	477	–	–	–
3 months	470	26 (5.5)	378 (80.4)	28 (5.9)	38 (8.1)
6 months	470	41 (8.7)	352 (74.9)	43 (9.1)	34 (7.2)

Table 3: Significant predictors of survival; HR, hazard ratio, CI, Confidential Index, AFP, alpha-fetoprotein, ALBI, albumin-Bilirubin grade, BCLC, Barcelona Clinic Liver Cancer staging system, mRECIST, Response Evaluation Criteria In Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

Variables		Univariate analysis		Multivariate analysis
Variables		HR (95% CI)	P value	HR (95% CI)	P value
Age (years)	<65	1,37 (0.86-2.1)	0.17	1,67 (0.87-3.18)	0.12
	≥65	1
Sex	Male	1.4 (0.67-2.9)	0.36	0.68 (0.21-2.27)	0.54
	Female	1
ECOG	0, 1	0.23 (0.14-0,39)	0.000
	≥2	1		2,75 (0.71-10.62)	0.142
Index lesion size (cm)	≤7	0.64 (0.41-1.02)	0.058	0,60 (0.33-1.08)	0.09
Index lesion size (cm)	>7	1
ALBI grade	Grade I	0.40 (0.23-0.72)	0.002	0.85 (0.42-1.74)	0.65
	Grade II, III	1
AFP	<200	1		0,85 (0,47-1,55)	0,59
	≥200	1.15 (0.68-1.95)	0.58
Child-Pugh class	Child A	0.23 (0.15-0.37)	0.000	0.37 (0.9-0.73)	0.004
	Child B, C	1
BCLC stage	A, B	0.47 (0.29-0.74)	0.001
	C, D	1		1.52 (0.75-3.04)	0.24
Tumor response (mRECIST)	CR/PR	0.05 (0.03-0.08)	0.000	0.04 (0.02-0.08)	0.000
Tumor response (mRECIST)	SD/PD	1

Table 4: Survival time of HCC patients underwent treatment of DEB-TACE

Study, year	n	Median OS (months)	The overall survival rates (%)
Study, year	n	Median OS (months)	1 year	2 years	3 years
Malagari et al, 2012 [14]	173	43.8	93.6	83.8	62
Song et al, 2012 [15]	60	32.2	88	-	-
Golfieri et al, 2014 [16]	89	29	86.2	56.8	-
Mukund et al, 2021[17]	25	28	92	57	-
Our study	477	53	89	-	78

No competing interests reported.

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Version 1

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You are reading this latest preprint version

Long-term survival outcomes of drug-eluting bead transarterial chemoembolization in patients with hepatocellular carcinoma in Vietnam

Status:

Version 1

Abstract

Aim

Methods

Results

Conclusion

Figures

Introduction

Results

Patient characteristics at the baseline

The treatment response

Factors affecting

Discussion

Patients and methods

Declarations

References

Tables

Additional Declarations

Status:

Version 1