Drug-eluting bead transarterial chemoembolization as neoadjuvant therapy pre-liver transplantation for advanced-stage hepatocellular carcinoma

Abstract

BACKGROUND

The objectives of this study were to assess the safety and efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) as neoadjuvant therapy before liver transplantation (LT) for advanced-stage hepatocellular carcinoma (HCC) and to analyze the prognostic factors.

AIM

To determine whether DEB-TACE before LT is superior to LT for advanced-stage HCC.

METHODS

A total of 99 individuals diagnosed with advanced HCC were studied retrospectively. The participants were categorized into the following two groups based on whether they had received DEB-TACE before LT: DEB-TACE group (n = 45) and control group (n = 54). The participants were further divided into two subgroups based on the presence or absence of segmental portal vein tumor thrombus (PVTT). The DEB-TACE group consisted of two subgroups: Group A (n = 31) without PVTT and group B (n = 14) with PVTT. The control group also had two subgroups: Group C (n = 37) without PVTT and group D (n = 17) with PVTT. Data on patient demographics, disease characteristics, therapy response, and adverse events (AEs) were collected. The overall survival (OS) and recurrence-free survival (RFS) rates were assessed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were conducted to determine the parameters that were independently related to OS and RFS.

RESULTS

The DEB-TACE group exhibited an overall response rate of 86.6%. Following therapy, there was a significant decrease in the median alpha-fetoprotein (AFP) level (275.1 ng/mL vs 41.7 ng/mL, P < 0.001). The main AE was post-embolization syndrome. The 2-year rates of RFS and OS were significantly higher in the DEB-TACE group than in the control group (68.9% vs 38.9%, P = 0.003; 86.7% vs 63.0%, P = 0.008). Within the subgroups, group A had higher 2-year rates of RFS and OS compared to group C (71.0% vs 45.9%, P = 0.038; 83.8% vs 62.2%, P = 0.047). The 2-year RFS rate of group B was markedly superior to that of group D (64.3% vs 23.5%, P = 0.002). Results from multivariate analyses showed that pre-LT DEB-TACE [hazard ratio (HR) = 2.73, 95% confidence interval (CI): 1.44-5.14, P = 0.04], overall target tumor diameter ≤ 7 cm (HR = 1.98, 95%CI: 1.05-3.75, P = 0.035), and AFP level ≤ 400 ng/mL (HR = 2.34; 95%CI: 1.30-4.19, P = 0.009) were significant risk factors for RFS. Additionally, pre-LT DEB-TACE (HR = 3.15, 95%CI: 1.43-6.96, P = 0.004) was identified as a significant risk factor for OS.

CONCLUSION

DEB-TACE is a safe and efficient therapy for advanced-stage HCC and also enhances patient survival after LT.

Key Words: Hepatocellular carcinoma; Liver transplantation; Portal vein tumor thrombus; Drug-eluting bead transarterial chemoembolization; Neoadjuvant treatment

Core Tip: This retrospective study investigated the value of drug-eluting bead transarterial chemoembolization (DEB-TACE) as neoadjuvant therapy pre-liver transplantation (LT) for advanced-stage hepatocellular carcinoma. We identified 99 relevant cases among our patient population and followed their overall survival (OS) and recurrence-free survival. The results indicated that DEB-TACE before LT may prolong OS and reduce recurrence rate.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common form of cancer and the third leading cause of cancer-related deaths worldwide, with an estimated 906000 diagnoses and 830000 deaths annually[1]. Significant risk factors associated with HCC include chronic hepatitis B virus or hepatitis C virus infection, intake of food contaminated with aflatoxin, high alcohol consumption, type 2 diabetes, obesity, and smoking[2].

Liver transplantation (LT) is the gold-standard treatment for unresectable early-stage HCC in the setting of cirrhosis[3]. It is widely recognized that LT provides excellent outcomes for patients with HCC who meet the Milan criteria (solitary tumor ≤ 5 cm in size or no more than three tumors, all < 3 cm in diameter)[4]. However, the Milan criteria are considered too strict, and the Hangzhou criteria (HC) are more suitable for patients with HCC in China. Despite the effectiveness of LT, the development of HCC is gradual and difficult to detect, and there is still a subset of patients beyond the HC, with 30%-40% of patients having portal vein tumor thrombus (PVTT) at the time of initial diagnosis[5-9]. Neoadjuvant therapy (downstaging or bridging) before LT not only prevents tumor progression and reduces the risk of withdrawal from the transplantation list but also improves the prognosis of patients after LT[10,11]. However, due to the scarcity of organs, there is a long waiting period for patients, specifically for those with advanced HCC. Tumor growth also leads to individuals missing the opportunity for transplantation.

Drug-eluting bead transarterial chemoembolization (DEB-TACE) has the advantages of low systemic toxicity, high intratumoral drug concentration, and long drug elution time, showing good pharmacokinetic performance and tolerability in advanced HCC, and has also proven effective as a bridging and downstaging treatment before LT[12-16]. Indeed, it has been employed in our hospital as a conversion therapy before hepatectomy or as a locoregional therapy for patients with unresectable HCC whose Child-Pugh classification is A or B. However, whether it can be used as neoadjuvant therapy for advanced HCC with or without PVTT before LT remains unclear. In this study, we retrospectively analyzed the prognosis of patients who received LT after DEB-TACE for advanced HCC and identified important prognostic factors.

MATERIALS AND METHODS

Patients

We retrospectively analyzed 99 patients with advanced HCC in Shulan (Hangzhou) Hospital (in Hangzhou, Zhejiang Province, China) between January 2017 and December 2022. The decision to perform DEB-TACE was made by a multidisciplinary team including hepatobiliary and pancreas surgeons, radiologists, and medical oncologists, according to the patient’s tumor stage, liver function, and need for bridging therapy before LT. Patients were divided into the DEB-TACE group and the control group according to whether they received DEB-TACE before LT. Patients in each group were further divided into two subgroups according to the presence or absence of PVTT. The diagnosis of HCC was based on imaging examinations including computer tomography, magnetic resonance imaging before LT, and histology after LT. This study was reviewed and approved by the Ethics Committee of Shulan (Hangzhou) Hospital.

DEB-TACE procedures

The Seldinger technique was used to access the common femoral artery, with insertion of a 5 F vascular sheath. The tumor blood supply was assessed using celiac and superior mesenteric artery angiography, and a 2.1-F microcatheter was super-selected for the tumor-supplying artery. The DEB-TACE procedure utilized 60 mg epirubicin loaded with 100-300 μm Callispheres^® microspheres (Jiangsu Hengrui Medicine Co., Ltd., Jiangsu Province, China) to conduct embolization. Polyvinyl alcohol particles or Embosphere^® microspheres (BioSphere Medical, Rockland, MA, United States) were used when the embolization endpoint was not achieved. Extrahepatic tumor blood-supplying arteries such as the inferior phrenic, intercostal, or internal mammary arteries were embolized using the same approach, with stasis or near stasis (sluggish) of blood flow as the endpoint of embolization (Figure 1).

Figure 1 Tumor staining. A: Abdominal arteriogram showing the arteries supplying the tumor, the tumor itself, portal vein tumor thrombus staining, and a portal fistula; B: Cessation of embolism with stasis in the artery supplying the tumor and the disappearance of tumor staining.

Data collection

Patient baseline clinical and demographic characteristics such as age, sex, Child-Pugh classification, Eastern Cooperative Oncology Group (ECOG) score, time to LT, microvascular invasion (MVI), macrovascular invasion (MAV), overall diameter of target tumors, alpha-fetoprotein (AFP) level, and tumor differentiation were recorded.

Postprocedural evaluation and follow-up

All patients received treatment at our hospital from the time of HCC diagnosis until the LT procedure and subsequent post-transplantation. Patient follow-up was initiated at 3-4 wk after DEB-TACE, at which time two senior radiologists assessed the treatment responses in patients using the modified response evaluation criteria in solid tumors[17], which included complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) (Figure 2). The overall response rate (ORR) (%) was defined as (CR + PR/total cases × 100%). A comparison was made between preoperative and postoperative alterations in AFP level in both the DEB-TACE group and its subgroups. The National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 was used for the evaluation of treatment-related adverse events (AEs). Patients were monitored after LT until December 2022. Overall survival (OS) was defined as the time from LT to either death or most recent follow-up. Recurrence-free survival (RFS) was defined as the time between LT and HCC recurrence.

Figure 2 The patient was treated with drug-eluting bead transcatheter arterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus. A and B: Visible intrahepatic mass (A) and obvious enhancement of portal vein tumor thrombus (PVTT) III (B); C and D: After drug-eluting bead transcatheter arterial chemoembolization, the mass (C) and PVTT (D) showed extensive necrosis (C), and enhanced computed tomography showed a few enhanced lesions in the arterial phase: Modified response evaluation criteria in solid tumors efficacy was evaluated for partial response.

Statistical analyses

SPSS Statistics 26.0 (IBM Corp., Armonk, NY, United States) was used for all statistical analyses. Continuous variables are reported as the mean and standard deviation or as the median and range, and were compared using the Student’s t-test or Mann-Whitney U test when appropriate. Categorical variables were reported as numbers and percentages and were compared using the χ² test or Fisher’s exact test. Survival outcomes were assessed with Kaplan-Meier curves and log-rank tests, whereas predictors of OS and RFS were identified using multivariate Cox proportional hazards regression models. P < 0.05 was considered statistically significant.

RESULTS

Patient baseline characteristics

A total of 99 patients were enrolled in this study and followed up until December 2022 (Table 1). The mean age was 52.6 ± 11.1 years, and 92 (92.9%) were male. All 99 patients had chronic viral hepatitis B. The majority of patients (n = 83, 83.8%) were Child-Pugh class A. Thirty-one (31.3%) patients had segmental PVTT. The median AFP level at admission was 94.7 ng/mL (12.8 ng/mL, 3561.1 ng/mL), and the median AFP level before LT was 41.7 ng/mL (8.0 ng/mL, 601.4 ng/mL). AFP was measured one final time before LT; in 74 (74.7%) patients, the AFP level was ≤ 400 ng/mL. The overall diameter of the target tumor was determined by postoperative pathological measurement; the median overall diameter was 8.0 cm (5.2 cm, 11.3 cm) in 46 (46.5%) patients, and the overall diameter of the target tumors was ≤ 7 cm. Regarding tumor grade, the majority of patients (n = 71, 71.7%) had moderately differentiated tumor cells. Patients were divided into the following two groups: DEB-TACE group (n = 45) and control group (n = 54). DEB-TACE was performed as needed, an average of about 1.3 times. The median time spent on the waiting list was longer in the DEB-TACE group than in the control group (2.0 months vs 1.0 months, P < 0.01). The majority of patients in both groups were Child-Pugh class A, but more patients were class B and C in the control group (A = 43, B = 2, C = 0 vs A = 40, B = 9, C = 4, P < 0.01). There were no statistically significant differences between the two groups in terms of age, sex, ECOG performance status score, MAV, AFP level at admission, AFP level before LT, overall diameter of target tumors, or tumor grade.

Table 1 Baseline patient demographic and disease characteristics.

Characteristics	Total, n = 99	DEB-TACE group, n = 45	Control group, n = 54	P value
Age in yr	52.6 ± 11.1	52.0 ± 12.1	53.0 ± 10.2	0.64
Sex				> 0.99
Male	92 (92.9)	42 (93.3)	50 (92.6)
Female	7 (7.1)	3 (6.7)	4 (7.4)
ECOG PS score				0.53
0	45 (45.5)	22 (48.9)	23 (42.6)
1	54 (54.5)	23 (51.1 )	31 (57.4)
HBV	99 (100.0)	45 (100.0)	54 (100.0)
Child­Pugh classification				< 0.01
A	83 (84.7)	43 (95.6)	40 (75.5)
B	11 (11.2)	2 (4.4)	9 (17.0)
C	4 (4.1)	0 (0.0)	4 (7.5)
Time to LT in month	1.0 (1.0, 2.0)	2.0 (1.0, 3.5)	1.0 (1.0, 1.0)	< 0.01
Macrovascular invasion				0.96
Negative	68 (68.7)	31 (68.9)	37 (68.5)
Segmental PVTT	31 (31.3)	14 (31.1)	17 (31.5)
AFP level at admission in ng/mL	94.7 (12.8, 3561.1)	275.1 (17.2, 5428.8)	43.1 (9.7, 455.2)	0.07
AFP level before LT in ng/mL	41.7 (8.0, 601.4)	41.7 (4.7, 619.7)	43.1 (9.7, 455.2)	0.61
AFP ≤ 400 ng/mL	74 (74.4)	32 (71.1)	42 (77.8)	0.44
AFP > 400 ng/mL	25 (25.3)	13 (28.9)	12 (22.2)
Overall diameter of target tumors in cm	8.0 (5.2, 11.3)	6.9 (4.7, 11.8)	8.0 (5.4, 11.0)	0.87
≤ 7 cm	46 (46.5)	24 (53.3)	22 (40.7)	0.21
> 7 cm	53 (53.5)	21 (46.7)	32 (59.3)
Tumor grade				0.97
Well differentiated	3 (3.0)	1 (2.2)	2 (3.7)
Moderately differentiated	71 (71.7)	33 (73.3)	38 (70.4)
Undifferentiated	25 (25.3)	11 (24.4)	14 (25.9)

Data are expressed as n (%) or mean ± SD. AFP: Alpha-fetoprotein; DEB-TACE: Drug-eluting bead transcatheter arterial chemoembolization; ECOG PS: Eastern Cooperative Oncology Group performance status; HBV: Hepatitis B virus; LT: Liver transplantation; PVTT: Portal vein tumor thrombus.

A notable disparity was found in the extent of MVI between the two groups of patients without segmental PVTT (DEB-TACE group vs control group, P < 0.01). Therefore, we divided the two groups of patients into four subgroups according to the presence or absence of PVTT. In the DEB-TACE group, group A (n = 31) consisted of patients without PVTT and group B (n = 14) included patients with PVTT. Similarly, the control group was also divided into two subgroups; group C (n = 37) comprised patients without PVTT, and group D (n = 17) included patients with PVTT. Tumor characteristics composed the preliminary analyses of the subgroups (Table 2).

Table 2 Baseline subgroup disease characteristics.

Characteristic	Without segmental PVTT		P value	With segmental PVTT		P value
	Group A, n = 31, 68.9%	Group C, n = 37, 68.5%		Group B, n = 14, 31.1%	Group D, n = 17, 31.5%
AFP level at admission in ng/mL	155.9 (11.9, 1386.6)	22.6 (7.2, 297.9)	0.121	5428.8 (33.5, 20000)	172.2 (54.5, 7951.4)	0.233
AFP level before LT in ng/mL	26.5 (4.6, 200.6)	22.6 (7.2, 297.9)	0.703	459.9 (4.6, 7670.5)	172.2 (54.5, 7951.4)	0.953
Overall diameter of target tumors in cm	6.3 (4.4, 9.6)	8.0 (4.9, 11.0)	0.449	9.4 (6.6, 16.6)	8.0 (6.1, 11.5)	0.361
Tumor grade, n (%)			0.925			> 0.99
Well differentiated	1 (3.2)	1 (2.7)		0 (0.0)	1 (5.9)
Moderately differentiated	22 (71.0)	27 (73.0)		11 (78.6)	11 (64.7)
Undifferentiated	8 (25.8)	9 (24.3)		3 (21.4)	5 (29.4)
MVI, n (%)			< 0.01			-
MVI = M0	13 (41.9)	11 (29.7)		-	-
MVI = M1	10 (32.3)	6 (16.2)		-	-
MVI = M2	8 (25.8)	20 (54.1)		-	-

AFP: Alpha-fetoprotein; LT: Liver transplantation; MVI: Microvascular invasion; PVTT: Portal vein tumor thrombus.

DEB-TACE responses and safety outcomes

With a 100% technical success rate, 10 (22.2%), 29 (64.5%), 1 (2.2%), and 5 (11.1%) patients achieved CR, PR, SD, and PD respectively, with ORR value of 86.6%. The DEB-TACE group and its subgroups showed a substantial decrease in AFP levels after therapy (Table 3). The most common AEs were post-embolization syndrome including moderate fever (87.5%), abdominal pain (74.7%), and nausea (57.5%). The majority of patients experienced temporary liver function impairment after DEB-TACE. None of the patients experienced severe treatment-related complications.

Table 3 Alpha-fetoprotein efficacy evaluation.

Group	AFP before treatment	AFP after treatment	Z	P value
DEB-TACE group in ng/mL	275.1 (17.2-5428.8)	41.7 (4.7-619.7)	-3.810	< 0.001
Group A in ng/mL	155.9 (11.9, 1386.6)	26.5 (4.6, 200.6)	-2.793	0.005
Group B in ng/mL	5428.8 (33.5, 20000)	459.9 (4.6, 7670.5)	-2.341	0.019

AFP: Alpha-fetoprotein; DEB-TACE: Drug-eluting bead transarterial chemoembolization.

Patient survival outcomes

The median post-transplantation follow-up in the DEB-TACE group was 37.0 months, ranging from 27.0 months to 57.0 months, and in the control group was 36.0 months, ranging from 18.0 months to 49.2 months (P = 0.085 compared to the DEB-TACE group). The 2-year RFS and OS were significantly higher in the DEB-TACE group (Figure 3A) than in the control group (Figure 4A) (RFS: 68.9% vs 38.9%, P = 0.003; OS: 86.7% vs 63.0%, P = 0.008). Meanwhile, the overall diameter of target tumors ≤ 7 cm (Figure 3B), AFP level ≤ 400 ng/mL (Figure 3C), and lack of MAV (Figure 3D) were observed to be associated with better RFS (log-rank < 0.05). The overall diameter of target tumors (Figure 4B) ≤ 7 cm was observed to be associated with better OS (log-rank < 0.05). We preliminarily observed the prognosis of patients in the subgroups. Without segmental PVTT, the 2-year RFS rate after LT was 71.0% and 45.9% in groups A and C respectively (P = 0.038; Figure 5A). With segmental PVTT, the 2-year RFS rate after LT was 64.3% and 23.5% in groups B and D respectively (P = 0.022; Figure 5B).

Figure 3 Kaplan-Meier analysis of survival outcomes in patients. A: Recurrence-free survival comparisons; B: Overall diameter of target tumors; C: Alpha-fetoprotein level before liver transplantation; D: Macrovascular invasion. DEB-TACE: Drug-eluting bead transcatheter arterial chemoembolization; AFP: Alpha-fetoprotein; LT: Liver transplantation.

Figure 4 Kaplan-Meier analysis of survival outcomes in patients. A: Overall survival comparisons; B: Overall diameter of target tumors. DEB-TACE: Drug-eluting bead transcatheter arterial chemoembolization.

Figure 5 Two-year recurrence-free survival rates and overall survival rates comparisons in subgroup analyses. A: Patients without portal vein tumor thrombus (PVTT); B: Patients with segmental PVTT.

Identification of independent predictors of patient OS and RFS

Multivariate analysis indicated that pre-LT DEB-TACE [hazard ratio (HR) = 2.73, 95% confidence interval (CI): 1.44-55.14, P = 0.002], overall diameter of target tumors ≤ 7 cm (HR = 1.98, 95%CI: 1.05-3.75, P = 0.035) and AFP level ≤ 400 ng/mL (HR = 2.27, 95%CI: 1.23-4.21, P = 0.009) were independent factors of tumor recurrence. Further exploration of the independent factors for predicting OS showed that pre-LT DEB-TACE (HR = 3.15, 95%CI: 1.43-6.96, P = 0.004) was an independent factor (Table 4).

Table 4 Univariate and multivariate Cox proportional hazards model for recurrence-free survival and overall survival.

Variable	Univariate analysis				Multivariate analysis
	Total, n	HR	95%CI	P value	HR	95%CI	P value
RFS
Pre-LT DEB-TACE as yes/no	45/54	2.62	1.41-4.89	0.002	2.73	1.44-5.14	0.002
Child-Pugh classification
A	83	Reference	N/A	N/A	N/A	N/A	N/A
B	12	2.03	0.98-4.23	0.056	N/A	N/A	N/A
C	4	1.52	0.36-6.35	0.559	N/A	N/A	N/A
Macrovascular invasion as yes/no	31/68	1.74	0.98-3.09	0.056	N/A	N/A	N/A
Overall diameter of target (tumors in cm for ≤ 7 cm/> 7 cm)	46/53	2.55	1.38-4.69	0.003	1.98	1.05-3.75	0.035
AFP of ≤ 400 ng/mL/> 400 ng/mL)	74/25	2.34	1.30-4.19	0.004	2.27	1.23-4.21	0.009
Tumor differentiation
Well differentiated	3	Reference	N/A	N/A	N/A	N/A	N/A
Moderately differentiated	71	1.42	0.19-10.45	0.726	N/A	N/A	N/A
Undifferentiated	25	2.27	0.30-17.13	0.426	N/A	N/A	N/A
OS
Pre-LT DEB-TACE as yes/no	45/54	3.33	1.51-7.34	0.003	3.15	1.43-6.96	0.004
Child-Pugh classification
A	83	Reference	N/A	N/A	N/A	N/A	N/A
B	12	2.46	1.06-5.68	0.035	N/A	N/A	N/A
C	4	1.81	0.42-7.66	0.41	N/A	N/A	N/A
Macrovascular invasion as yes/no	31/68	1.25	0.62-2.48	0.524	N/A	N/A	N/A
Overall diameter of target (tumors in cm of ≤ 7 cm/> 7 cm)	46/53	2.09	1.02-4.28	0.042	N/A	N/A	N/A
AFP of ≤ 400 ng/mL/> 400 ng/mL	74/25	1.68	0.83-3.39	0.145	N/A	N/A	N/A
Tumor differentiation
Well differentiated	3	Reference	N/A	N/A	N/A	N/A	N/A
Moderately differentiated	71	N/A	NA1	0.922	N/A	N/A	N/A
Undifferentiated	25	N/A	NA1	0.920	N/A	N/A	N/A

¹Heart rate calculation and inclusion of the covariate in univariate analysis was not applicable due to the lack of hepatocellular carcinoma deaths in the well-differentiated group.

RFS: Recurrence-free survival; 95%CI: 95% confidence interval; AFP: Alpha-fetoprotein; DEB-TACE: Drug-eluting bead transcatheter arterial chemoembolization; HR: Hazard ratio; LT: Liver transplantation; N/A: Not applicable; OS: Overall survival; NA: Not available.

DISCUSSION

Liver resection is superior to non-surgical treatment for advanced HCC in terms of survival outcome, particularly in patients with segmental PVTT; therefore, it is recommended as the primary therapeutic option for patients with a well-functioning liver[18]. However, even PVTT is limited to the first-order branch. Shi et al[19] found that with surgical resection or palliative resection, the 3-year OS rate was less than 30%. In phase 3 trials of lenvatinib and sorafenib for systemic treatment of unresectable HCC, the median OS was 13.6 months and 12.3 months respectively[3,20]. For patients with PVTT but demonstrating satisfactory liver function, TACE is not a contraindication and is safe and effective in terms of efficacy, especially DEB-TACE as locoregional therapy, showing a non-inferior median OS of 12.3 months compared with systemic therapy[21,22].

In our study, the median total diameter of the target tumor in the DEB-TACE group was 6.9 cm, and 31.3% of patients had segmental PVTT. Nevertheless, DEB-TACE still showed an extremely high ORR, especially after neoadjuvant therapy when the median AFP decreased from 275.1 ng/mL to 41.7 ng/mL. The postoperative AEs primarily presented as post-embolization syndrome, and all patients experienced alleviation following the administration of symptomatic therapy, with no severe AEs observed. Liver function impairment was transient, and all patients experienced a full recovery following liver protective measures. Thus, DEB-TACE showed high efficacy and tolerability in patients with advanced HCC.

In 1996, Mazzaferro et al[4] established the Milan criteria as a standardized method for LT, resulting in 4-year OS and RFS rates of 83% and 75% respectively. In China, HC is not limited to tumor size and number but also introduces tumor differentiation and AFP as reference for tumor biological behavior, resulting in 3-year OS and RFS rates of 81.9% and 78.8% respectively. However, 30% of patients exceed the HC, and PVTT is observed in 44%-62.2% of HCC patients[5,23,24]. In the absence of effective treatment, the duration of PVTT progression from type I to II and type II to III is 8.2 d and 11.5 d respectively, with a median OS of only 2-4 months[1]. Hence, selecting an effective therapy to diminish the tumor burden and manage the advancement of PVTT before LT is of utmost significance.

Previous investigations have shown that HCC with PVTT is a risk factor for poor prognosis and a contraindication to LT[25,26]. However, some researchers believe that segmental PVTT does not inevitably cause immediate distant metastases, and patients with low AFP levels, well-differentiated tumors, and a strong response to neoadjuvant therapy can still benefit from LT[27]. Lee et al[7] found a 3-year RFS rate of 45.5% and 3-year OS rate of 63.6% after LT for HCC with PVTT. Further reports by Choi et al[6] showed that for segmental PVTT, the 3-year RFS and OS rates were 63.9% and 60.3%. In our study, both the 2-year RFS (68.9% vs 38.9%) and OS (86.7% vs 63.0%) rates were higher in the DEB-TACE group than in the control group. However, in the subgroups, especially in patients with PVTT, there were significant differences in RFS rate between group B (64.3%) and group D (23.5%). The 2-year OS rate of group B was still higher than that of group D, although there was no statistically significant difference between the two groups.

We observed an interesting result in the subgroups without PVTT. AFP and MVI can be used as references for tumor biological behavior and are predictors of recurrence and mortality, and patients’ AFP levels are remarkably higher with vascular invasion[28-30]. However, in our study, the median AFP level of group A was significantly higher than that of group C at admission, and patients who received DEB-TACE in group A were more likely to have poor tumor characteristics. The pathological results after LT showed that there was no significant difference in the degree of tumor differentiation between the two groups, but the degree of MVI in group A was lower than that of group C. Regarding whether this was related to the receipt of neoadjuvant therapy, we hypothesize that DEB-TACE can reverse the degree of MVI; however, this theory needs to be confirmed by further studies.

As indicated by multivariate analyses, DEB-TACE pre-LT, AFP level, and overall diameter of target tumors were independent factors for recurrence. More importantly, we found that the DEB-TACE pre-LT was an independent factor for OS. Therefore, we believe that DEB-TACE as neoadjuvant therapy can also improve the prognosis of patients after LT.

This study had some limitations. First, the sample size of the study was small, with patients only from China. Second, for advanced HCC, DEB-TACE as neoadjuvant therapy before LT was not combined with systemic therapy; such combination therapy could lead to better outcomes and thus needs further study.

CONCLUSION

In our study, DEB-TACE as neoadjuvant therapy before LT was tolerant and effective, revealing a good clinical outcome. Segmental PVTT should not be an absolute contraindication for patients who respond well to neoadjuvant therapy LT.