Efficacy and safety of transcatheter arterial chemoembolization combined with either 125I seed implantation or apatinib in hepatocellular carcinoma with portal vein tumor thrombosis: A retrospective comparative study

Yuanyuan Li; Hailiang Li; Hongtao Hu; Hang Yuan; Yan Zhao

doi:10.4103/jcrt.JCRT_1587_20

ORIGINAL ARTICLE

Year : 2020 | Volume : 16 | Issue : 7 | Page : 1691-1697

Efficacy and safety of transcatheter arterial chemoembolization combined with either ¹²⁵I seed implantation or apatinib in hepatocellular carcinoma with portal vein tumor thrombosis: A retrospective comparative study

Yuanyuan Li, Hailiang Li, Hongtao Hu, Hang Yuan, Yan Zhao
Minimally Invasive and Interventional Department, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China

Date of Submission	28-Oct-2020
Date of Decision	03-Dec-2020
Date of Acceptance	31-Dec-2020
Date of Web Publication	9-Feb-2021

Correspondence Address:
Hailiang Li
The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jcrt.JCRT_1587_20

> Abstract

Aims: The aims of the study were to compare the efficacy and safety between transcatheter arterial chemoembolization (TACE) combined with ¹²⁵I seed implantation (TACE-¹²⁵I) or with apatinib (TACE-Apatinib) in HCC-portal vein tumor thrombosis (PVTT) patients.
Setting and Design: We retrospectively evaluated the medical records of consecutive patients with HCC-PVTT who had undergone treatment with either TACE-¹²⁵I or TACE-Apatinib between January 2018 and June 2019.
Materials and Methods: The response was assessed at the last follow-up, and the outcomes were compared between the two groups. Progression-free survival (PFS), overall survival (OS), and treatment-related complications were evaluated. Statistical analysis used the 2-sample Student's t-test and Fisher's exact test.
Results: This study enrolled 48 patients; 21 were treated with TACE-Apatinib and 27 with TACE-¹²⁵I. For PVTT, the disease control rate (DCR) was 23.81% in the TACE-Apatinib group and 77.78% in the TACE-¹²⁵I group. The objective response rate (ORR) in the TACE-Apatinib group was remarkably lower. The DCR of intrahepatic lesions was 85.71% in the TACE-Apatinib group and 81.48% in the TACE-¹²⁵I group. There was no statistically significant difference in the ORR of intrahepatic lesions. Median OS was significantly longer in the TACE-¹²⁵I group (13.3 vs. 10.8 months). Similarly, the median PFS was significantly longer in the TACE-¹²⁵I group (9.7. vs. 6.6 months). Multivariate and univariate analyses showed that TACE-¹²⁵I was an independent prognostic factor for OS.
Conclusions: Compared with TACE-Apatinib, TACE-¹²⁵I seed implantation can effectively prolong PVTT progression, PFS, and OS in HCC patients with PVTT.

Keywords: ¹²⁵I seed implantation, apatinib, hepatocellular carcinoma, portal vein tumor thrombosis, retrospective study, transcatheter arterial chemoembolization

How to cite this article:
Li Y, Li H, Hu H, Yuan H, Zhao Y. Efficacy and safety of transcatheter arterial chemoembolization combined with either ¹²⁵I seed implantation or apatinib in hepatocellular carcinoma with portal vein tumor thrombosis: A retrospective comparative study. J Can Res Ther 2020;16:1691-7

How to cite this URL:
Li Y, Li H, Hu H, Yuan H, Zhao Y. Efficacy and safety of transcatheter arterial chemoembolization combined with either ¹²⁵I seed implantation or apatinib in hepatocellular carcinoma with portal vein tumor thrombosis: A retrospective comparative study. J Can Res Ther [serial online] 2020 [cited 2021 Feb 28];16:1691-7. Available from: https://www.cancerjournal.net/text.asp?2020/16/7/1691/308763

> Introduction

Liver cancer is the fourth most common cause of death and the fifth most common cancer globally. Hepatocellular carcinoma (HCC) represents approximately 90% of primary liver cancers and constitutes a major global health problem.^[1],[2] Unfortunately, more than 40% of HCC patients are diagnosed with stage C liver cancer according to the Barcelona Clinical Liver Cancer staging system due to an extremely long incubation period.^[3] Of these cases, 62.2%–90.0% are associated with portal vein tumor thrombosis (PVTT) and have a very short median survival time if left untreated.^[4] Although sorafenib is recommended as the first-line therapy for advanced HCC, the efficacy of this drug is not satisfactory for Asian patients with advanced HCC.^[1],[5] The most valid treatment for advanced HCC is transcatheter arterial chemoembolization (TACE). Multiple studies have confirmed that TACE can prolong disease progression and improve survival prognosis in patients with advanced HCC.^[6],[7] However, studies have confirmed that the level of vascular endothelial growth factor (VEGF) in local residual tumor tissues was significantly increased after TACE treatment due to hypoxia, which further stimulated tumor angiogenesis and led to tumor recurrence and metastasis.^[8],[9] Apatinib is a novel VEGF receptor (VEGFR)-2 inhibitor with the highest known selectivity, and its binding affinity for VEGFR-2 tyrosine kinase is 10 times higher than that of sorafenib.^[10] Apatinib also inhibits multiple ATP binding sites, reverses multidrug resistance, and improves the efficacy of conventional chemotherapy drugs.^[11],[12] Therefore, apatinib can effectively inhibit VEGF after TACE treatment and increase the therapeutic effect. In addition, TACE combined with apatinib has been confirmed to prolong overall survival (OS) in patients with HCC-PVTT.^[13]

Since HCC is radiosensitive,^[14] ¹²⁵I seeds have been widely applied for the treatment of prostate cancer, head tumors, and HCC.^[15],[16] The feasibility and effectiveness of TACE combined with ¹²⁵I seeds (TACE-¹²⁵I) in patients with PVTT have been established.^[17] In addition, Hu's group indicated that TACE-¹²⁵I seed implantation could significantly prolong the OS in patients with PVTT.^[18] However, at present, the study of ¹²⁵I in the treatment of PVTT is still in its early stages, and few relevant studies have been reported. Since the disease is insidious, most patients with PVTT present with invasion already to the first-level branch; thus, the focus of this study was on patients with this type of PVTT. We conducted a retrospective cohort analysis of HCC patients with PVTT occurring only in the right or left portal vein and evaluated the efficacy and safety of TACE-¹²⁵I and compared it with that of TACE combined with apatinib (TACE-Apatinib).

> Materials and Methods

Study design

Patient selection

We retrospectively reviewed the electronic medical records of 89 patients with advanced HCC-PVTT treated with either TACE-¹²⁵I or TACE-Apatinib, at the Henan Cancer Hospital of China, from January 2018 to June 2019. All patients were diagnosed according to the guidelines of the American Association for the Study of Liver Disease.^[19] The study was approved by the local ethics committee and was performed in accordance with the Declaration of Helsinki. All the patients signed consents before operations and were informed about the TACE procedure, anesthesia, and complications.

Inclusion criteria

Aged 18–75 years;
Barcelona clinic liver cancer classification stage B or stage C;
Computed tomography (CT) or magnetic resonance imaging (MRI) showing PVTT on the left or right side of the portal vein;
Eastern Cooperative Oncology Group (ECOG) performance status 0–1; and
Child–Pugh liver function class A or B.

Exclusion criteria

Complete obstruction of the portal vein;
Other surgeries, ablation treatment, systemic chemotherapy, or TACE;
Severe coagulation disorders;
Severe dysfunction of important organs, such as the heart, lungs, kidneys, and other organs; and
Other malignant tumors.

Classification of portal vein tumor thrombosis

Based on previous research, PVTT was classified into three subgroups: (1) Type A = PVTT in the main portal vein; (2) Type B = PVTT in the first-order portal vein branch (the right or left portal vein); and (3) Type C = PVTT in the second-or lower-order portal vein branches.^[20],[21] Based on research requirements, all Type B PVTT patients were enrolled in the study.

Treatment schedule

First, the patients were administered apatinib 4 days after each TACE treatment and were paused for 4 days before the next TACE in the TACE-Apatinib group. Apatinib was taken at a dose of 500 mg/day and adjusted according to the severity of toxicity. If the initial dose was not well tolerated or adverse reactions occurred, the dose would be adjusted to 250 mg. Once the patient stabilized and the adverse reactions ceased, the dose was increased to the original level. Then, TACE was performed by one of three physicians (LHL, GCY, and HHT) according to a previously reported method.^[18] If the contrast-enhanced CT or MRI scans showed an intrahepatic recurrent tumor or residual viable tumor, the TACE procedure was repeated.

Implantation of ¹²⁵I seeds

The target area was determined by CT scan before TACE treatment [Figure 1], and the image was an input to the treatment planning system (TPS, FTT Technology Co, Ltd., Beijing, China). To obtain the best dose distribution diagram, the ¹²⁵I seed dose distribution, guide needle location, and ¹²⁵I seed location were determined using the TPS. Next, the patient was placed in the supine or prone position according to the lesion location, and the needle entry point, angle, depth, and other puncture parameters were redetermined by CT scan. Guided by the TPS, an 18G seed implantation needle was used to puncture lesions, and ¹²⁵I seeds (Tianjin Union Medical Science and Technology Co., China) were implanted at different levels and locations of the PVTT to produce an even distribution of seeds [Figure 2] and [Figure 3]. The ¹²⁵I seeds were implanted evenly into the PVTT under the guidance of the TPS. The aim was to reach a prescribed dose of 100–150 Gy in 90% of the tumor target volume. In addition, ¹²⁵I seed implantation was repeated if residual viable or recurrent PVTT was detected.

Figure 1: Magnetic resonance imaging image before 125I seed implantation

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Figure 2: ¹²⁵I seed implantation was performing

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Figure 3: ¹²⁵I seed implantation was performed

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Follow-up

We performed a series of follow-up examinations on all patients. Each follow-up session consisted of a detailed history, abdominal contrast-enhanced CT or MRI [Figure 4], and hematological and biochemical analyses including total bilirubin, serum albumin, and prothrombin time. The first follow-up was conducted 4 weeks after the first TACE, and subsequent follow-ups were every 8 weeks after the initial follow-up.

Figure 4: Magnetic resonance imaging image 3 months after ¹²⁵I seed implantation

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Patient assessment

We reviewed the clinical, laboratory, and radiologic records. We assessed and graded serious adverse events according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0).^[21] We compared the median OS and the progression-free survival (PFS) between TACE-¹²⁵I- and TACE-Apatinib-treated patients. We defined OS as the time from the first TACE procedure until death from any cause or the last follow-up. PFS was defined as the absence of new intrahepatic or extrahepatic lesions, local progression, or death. The treatment response for intrahepatic tumor lesions was assessed based on the modified Response Evaluation Criteria in Solid Tumors.^[22] A new system was used to categorize PVTT responses based on CT scans or MRI. The categories were as follows: (1) complete response and PVTT disappearance; (2) partial response, PVTT disappearance, or a >30% reduction in thrombus in the greatest cross-sectional area; (3) stable disease and ≤30% reduction in thrombus in the greatest cross-sectional area; and (4) progressive disease and extended thrombus.^[23]

Statistical analysis

All statistical analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). Student's t-test, the Chi-square test, and Fisher's exact test were used to determine statistically significant differences in survival between the two groups. The survival curves were plotted using the Kaplan–Meier method, and the survival rate and median survival were estimated. The survival curves were compared between groups using the log-rank test. Univariate analysis was used for initial screening to identify prognostic factors. A multivariate Cox proportional hazard regression model was used to screen the independent factors affecting prognosis, which were represented by risk ratio and 95% confidence interval. P < 0.05 was considered significant.

> Results

Patient characteristics

We evaluated the medical records of 89 HCC patients with type B PVTT who underwent either TACE-Apatinib or TACE-¹²⁵I treatment from January 2018 to June 2019. However, 41 patients were excluded, while 48 met the eligibility criteria and were included in the analysis; 21 underwent TACE-Apatinib, while 27 underwent TACE-¹²⁵I, as indicated in [Figure 5]. Detailed baseline patient characteristics are presented in [Table 1]. There were no significant intergroup differences in any of the parameters.

Figure 5: Flow diagram of the study. The diagram shows exclusion criteria in hepatocellular carcinoma patients with portal vein tumor thrombosis. ¹²⁵I = ¹²⁵I seed implantation, RFA = Radiofrequency ablation, TACE = Transarterial chemoembolization

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Table 1: Baseline patient characteristics

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During follow-up, 20 patients (95.2%) in the TACE-Apatinib group and 25 (92.6%) in the TACE-¹²⁵I group died. All 48 patients successfully completed at least one TACE treatment. The duration of the procedure in the TACE-Apatinib group was obviously higher than that in the TACE-¹²⁵I group (5.1 ± 1.7 vs. 4.0 ± 1.5 h, P = 0.03). Six patients (22.2%) in the TACE-¹²⁵I group received repeated ¹²⁵I seed implantation. Two patients (7.4%) had needle hemorrhage but recovered well after treatment.

Efficacy

No CRs were observed after follow-up based on CT or MRI scans. For PVTT, the disease control rate (DCR) in the TACE-Apatinib group was 23.81%, and in the TACE-¹²⁵I group, it was 77.78% (P < 0.05). The objective response rate (ORR) in the TACE-Apatinib group was significantly lower than that in the TACE-¹²⁵I group (4.76% vs. 40.74%, P = 0.012). The intrahepatic lesions in the TACE-Apatinib group showed a DCR not significantly different from that in the TACE-¹²⁵I group (85.71% vs. 81.48%, P > 0.05). We observed no significant group-wise differences in the ORR of intrahepatic lesions (66.67% vs. 59.26%, P = 0.599) [Table 2].

Table 2: Group-wise comparisons of tumor responses in portal vein tumor thrombosis and intrahepatic lesions

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The effect of seed implantation on liver function is summarized in [Table 3]. Four weeks after ¹²⁵I seed implantation, total bilirubin, albumin, and prothrombin time had not changed significantly. However, after 12 weeks, the total bilirubin value had significantly decreased compared with baseline.

Table 3: Liver function changes in the transcatheter arterial chemoembolization-¹²⁵I group

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We found that the median OS was significantly better in the TACE-¹²⁵I group than in the TACE-Apatinib group at the end of the follow-up (13.3 months, 95% CI = 12.6–14.0 vs. 10.8 months, 95% CI = 9.9–11.7; t = 6.559, P = 0.010). Similarly, the median PFS was also significantly longer in the TACE-¹²⁵I group than in the TACE-Apatinib group (9.7 months, 95% CI = 7.4–12.0 vs. 6.6 months, 95% CI = 4.2–9.0; t = 4.970, P = 0.026) [Figure 6].

Figure 6: (a and b) Comparison of overall survival and progression-free survival between the TACE-Apatinib and TACE-¹²⁵I groups. TACE = Transarterial chemoembolization

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Factors affecting overall survival

We performed univariate and multivariate analyses to determine the prognostic factors for OS [Table 4]. Univariate analysis revealed that patients who underwent TACE-¹²⁵I treatment demonstrated better OS than did those who underwent TACE-Apatinib treatment (P < 0.05). Moreover, multivariate analysis demonstrated that treatment was an independent prognostic factor for OS (hazard ratio = 0.455; 95% CI = 0.245–0.848, P < 0.05).

Table 4: Univariate and multivariate analyses of prognostic factor for overall survival

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Adverse events

After TACE treatment, both the groups showed symptoms of abdominal pain, fever, nausea, and vomiting to varying degrees, while the difference between the two groups was not statistically significant (P > 0.05). In the TACE-Apatinib group, the common adverse reactions to apatinib were oral ulcer (4 cases), fatigue (6 cases), hypertension (7 cases), hand–foot syndrome (10 cases), proteinuria (5 cases), and diarrhea (7 cases), among which 3 adverse events were observed in 11 cases. In all patients with grade 3 adverse events, the dose of apatinib was reduced to 250 mg. In the TACE-¹²⁵I group, subcapsular hemorrhage of the liver was observed in 3 patients (11.1%), while grade 3 or grade 4 adverse events were not observed. The relevant adverse events are shown in [Table 5].

Table 5: Adverse events

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> Discussion

PVTT forms when tumor tissue breaks through the wall of the portal vein and enters the vascular lumen, which may cause complications related to portal hypertension, increased levels of the HCC marker alpha-fetoprotein (AFP), and even invasion of the inferior vena cava, leading to pulmonary embolism and sudden death, which are important factors affecting survival.^[24] The results of our study showed that TACE-¹²⁵I was associated with better efficacy than was TACE-Apatinib in patients with HCC-PVTT. In the TACE-¹²⁵I group, the PVTT, DCR, and ORR were higher, and the median OS and median PFS were significantly longer. The results of the univariate and multivariate analysis showed that treatment with TACE-¹²⁵I is a favorable independent factor for OS. These results indicated that TACE combined with ¹²⁵I seed implants may improve the OS in HCC patients with PVTT.

In addition, the most common adverse reactions to the TACE-¹²⁵I procedure, namely puncture site pain and seed transmigration, were manageable. TACE-related complications were not statistically significant between the two groups, indicating that the ¹²⁵I seed implants did not increase the occurrence rate of TACE-related adverse events. In general, ¹²⁵I seed implants can be tolerated by most patients.

This result showed that ¹²⁵I seed implants could improve the longer-term follow-up. In addition, we found that the number of TACE operations required by the TACE-Apatinib group was significantly greater than the TACE-¹²⁵I group. This may imply that TACE-Apatinib could not efficiently control the progress of PVTT or intrahepatic lesions, resulting in a requirement for more TACE procedures than needed by the TACE-¹²⁵I group. However, in more than half of the patients in the TACE-Apatinib group, the dose of apatinib had been decreased to deal with adverse reactions, which may have weakened the observed effect of apatinib. Additional testing is needed to clarify this.

These results demonstrated that TACE-¹²⁵I was efficient and safe for HCC patients with PVTT in the right or left portal vein branches. However, it is not appropriate to use ¹²⁵I seed implantation to treat patients whose PVTT invades the portal vein trunk and superior mesenteric vein because of the great technical difficulty and associated risks, which often prevent a uniform distribution of radiation dose.

Previous studies have shown that ¹²⁵I seed implantation could stimulate cellular immune function, strengthen the body's immunity to tumor cells, and kill tumor cells, effectively reducing the serum AFP level, so that patients benefit from treatment and have an improved prognosis.^[25] The finding that TACE-¹²⁵I is an independent factor for OS in HCC patients also indicated that TACE-¹²⁵I seed implantation is an effective regimen for the treatment of PVTT. The prescribed dose of ¹²⁵I radiation (30–60 Gy) is much higher than the tolerance dose of liver tissue, and the effective distance of irradiation is only 1.7 cm. As long as the ¹²⁵I seed is accurately implanted in the PVTT or within 1.7 cm of it, it can continue illuminating the tumor cells at close range for an extended period while not damaging normal liver cells, which is the biggest advantage of ¹²⁵I seed implantation over three-dimensional conformal radiation therapy. In this study, based on TACE embolization for blood supply of intrahepatic tumors and PVTT, irradiation by ¹²⁵I seeds proved more helpful in killing or inhibiting residual cancer cells after TACE treatment. The implanted ¹²⁵I seeds continuously emit radiation, bringing about the destruction of tumor cells to achieve effective treatment and control of PVTT and intrahepatic tumor.^[26],[27]

Finally, it should be borne in mind that this was a retrospective study. All patients had advanced HCC-PVTT and the therapeutic options were chosen according to the preference of the physician. Moreover, the sample size of this study was small, so the presence of an inherent bias cannot be ruled out. Thus, we recommend large prospective multicenter studies to evaluate the efficacy of TACE-¹²⁵I treatment in HCC patients with PVTT.

> Conclusions

TACE-¹²⁵I treatment demonstrated favorable safety and efficacy in HCC patients with PVTT and provided a longer OS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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