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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 619-624

Anlotinib followed by transarterial chemoembolization and radiofrequency ablation is a safe and effective initial treatment for hepatocellular carcinoma patients with portal vein tumor thrombus: A retrospective case series study


1 Department of Oncology, First People's Hospital of Foshan, Foshan Hospital of Sun Yat-Sen University, Foshan, China
2 Department of Interventional Radiology, Guangzhou First People's Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, China
3 Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China

Date of Submission27-Aug-2020
Date of Decision13-Oct-2020
Date of Acceptance05-Feb-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Jiren Zhang
Department of Oncology, Zhujiang Hospital, Southern Medical University, No. 253 Gongyedadao Middle Road, Guangzhou, 510060
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1253_20

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 > Abstract 


Background: Portal vein tumor thrombus (PVTT) remains a poor prognostic factor occurring in about 10%–40% of patients with hepatocellular carcinoma (HCC) for the optimal treatment is controversial. Anlotinib is an novel small molecule inhibitor that has a broad spectrum of inhibitory activities on tumor angiogenesis and growth. However, so far, no studies have reported the use of anlotinib in the treatment of HCC patients with PVTT. Here, we evaluated the safety and efficacy of anlotinib, followed by transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for the treatment of patients with HCC and PVTT.
Materials and Methods: A total of 145 consecutive HCC patients who underwent TACE in combination with RFA were enrolled in the retrospective study. Twenty-eight patients were diagnosed with PVTT and received anlotinib as basic treatment. The adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs Version 4.0. Time to tumor progression (TTP) and overall survival (OS) were calculated using the Kaplan–Meier method.
Results: The most common toxicities related to anlotinib were pharyngalgia (53.6%), fatigue (42.9%), and hand–foot skin reaction (39.3%). The median OS was 13 months (range: 3–18 months) with 1-year OS rate of 64.3%. The median TTP was 7 months (range: 1–12 months) with 6-month rate of 46.4%.
Conclusion: Anlotinib followed by TACE and RFA is a safe and effective initial treatment modality for HCC patients with PVTT. Anlotinib may be a promising therapeutic option for relieving and/or stabilizing HCC with PVTT.

Keywords: Anlotinib, hepatocellular carcinoma, portal vein tumor thrombus, radiofrequency ablation, transarterial chemoembolizationa


How to cite this article:
Wang J, Li X, Wang F, Shi D, Zhang J. Anlotinib followed by transarterial chemoembolization and radiofrequency ablation is a safe and effective initial treatment for hepatocellular carcinoma patients with portal vein tumor thrombus: A retrospective case series study. J Can Res Ther 2021;17:619-24

How to cite this URL:
Wang J, Li X, Wang F, Shi D, Zhang J. Anlotinib followed by transarterial chemoembolization and radiofrequency ablation is a safe and effective initial treatment for hepatocellular carcinoma patients with portal vein tumor thrombus: A retrospective case series study. J Can Res Ther [serial online] 2021 [cited 2021 Dec 9];17:619-24. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/619/321007




 > Introduction Top


Portal vein tumor thrombus (PVTT) remains a strongest negative prognostic factor for hepatocellular carcinoma (HCC).[1],[2],[3] Transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for HCC with PVTT showed effective results in modest.[4],[5],[6],[7],[8],[9] Sorafenib was the only target agent for these patients with about 6 months in survival time restricted by the poor tolerance.[10],[11] Anlotinib is a novel multitargeting tyrosine kinase inhibitor and has been examined safety and valid on HCC in China.[12],[13] TACE in combination with RFA resulted a synergistic outcome in treating HCC.[14] Retrospectively, we evaluated the safety and efficacy of anlotinib, followed by TACE and RFA for the treatment of HCC with PVTT.


 > Materials and Methods Top


Patients

All procedures involving human participants and the study protocol were in accordance with the ethical standards of the Research Ethics Committee of our hospital and the 1964 Helsinki Declaration. Informed consent was obtained from all patients before all treatments.

A total of 145 consecutive HCC patients who underwent TACE in combination with RFA between February 1, 2018, and August 31, 2019, were enrolled in the study. Among them, 28 patients were diagnosed with PVTT and consequently received anlotinib as basic treatment. The process of patients' selection is shown in [Figure 1]. The diagnosis of HCC was confirmed by histopathology and/or imaging studies, consisting of computed tomography (CT) scan, angiography, and magnetic resonance imaging and/or high plasma levels of alpha-fetoprotein (AFP). The presence of PVTT was diagnosed according to the following criteria: (1) a low-attenuation intraluminal mass that expanded the portal vein or portal branch on ultrasound or enhanced CT scan; (2) the “thread-and-streaks” sign or arterioportal shunts on hepatic angiography; or (3) filling defects in the portal vein or in the portal branch of an indirect portogram obtained from a venous phase angiogram of the superior mesenteric artery.
Figure 1: Flow diagram shows patient selection criteria and procession

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The inclusion criteria were the following: liver function of Child–Pugh Class A or B, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and prediction of survival time longer than 3 months. On the basis of the criteria of the Liver Cancer Study Group of Japan, the PVTT was divided into four types: VP1, Vp2, Vp3, and Vp4 (Vp0, no PVTT; Vp1, tumor thrombus in a third or more of peripheral branches of the portal vein; Vp2, tumor thrombus in a second branch of the portal vein; Vp3, tumor thrombus in the first branch of the portal vein; and Vp4, tumor thrombus in the trunk of the portal vein. The HCC patients with PVTT in type of Vp2, Vp3, and Vp4 were enrolled in the present study.

The exclusion criteria were: (1) patients who received other types of treatment including palliative resection, radiotherapy, hepatic arterial infusion chemotherapy, and sorafenib and (2) the extrahepatic metastasis that could not be controlled. The baseline characteristics of the 28 enrolled patients are displayed in [Figure 1].

Treatments

All treatments were performed at our hospital. Pretreatment evaluations included complete patient history, physical examination, and chest radiography; laboratory data included blood cell count, prothrombin time, and creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase, and serum AFP levels. In addition, all patients underwent preoperative hepatic contrast-enhanced CT scan or a positron emission tomography (PET)-CT at baseline and 1 month after therapy to evaluate the efficacy of the treatments.

Anlotinib was taken before the performance of TACE and RFA as basic treatment. The decision to perform TACE and RFA was based on the results of diagnostic imaging tests. RFA was sequentially performed 3–4 weeks after TACE when the residual lesion was detected by poor deposition of lipiodol emulsion in the lesion. The first TACE procedure was performed more than 14 days after anlotinib. Subsequent cycles of TACE and RFA were repeated every 3–6 weeks until viable intrahepatic tumor was not visible anymore or the patient could not accept treatment after evaluation. Throughout the procedures, the patients' vital signs (blood pressure, heart rate, and oxygen saturation) were monitored. All patients were observed for 6 h after returning to the recovery ward.

Transarterial chemoembolization procedure

TACE was performed using digital subtraction angiography with a SIEMENS Artis zee III ceiling 1000MA triode (Munich, German). A selective 5-Fr catheter (1.667 mm in diameter and 100 cm in length, Terumo, Tokyo, Japan) was inserted in the femoral artery using Seldinger technique. A visceral angiography was performed to assess the portal vein patency and to identify the arterial blood supply to the tumor. All patients underwent distal superselective catheterization of the hepatic arteries using a coaxial technique and a 2.8-Fr microcatheter (Terumo, Tokyo, Japan). Once the catheter was placed, chemolipiodolization was achieved using 40–60 mg epirubicin (Pharmorubicin; Pfizer, Wuxi, China) and 4–8 mg mitomycin C (Zhejiang Hisun Pharmaceutical, Taizhou, China) mixed with 5–20 mL of lipiodol (Lipiodol Ultra-Fluide; André Guerbet Laboratories, Aulnay-Sous-Bois, France). If the region of the chemolipiodolized artery did not show stagnant flow, pure iodized oil was injected to achieve stasis in the tumor-feeding artery. For all cases, embolization was performed with polyvinyl alcohol particles (Alicon Pharm SCT and TEC, Hangzhou, China, 350–560 μm in diameter). The injection dose of emulsion was determined by the size and vascularity of the target tumor. The injection was stopped when the full dose of the emulsion was administered or when the vasculature displayed 90% stasis of the emulsion on the arteriogram.

Radiofrequency ablation procedure

All RFA procedures were performed under intravenous general anesthesia. All lesions were monitored by CT imaging (Marconi CT-Twin flash, 120 kV and 265 mA, 5.0–10.0 mm slice thickness and 0.5 pitch or with Toshiba Aquilion TSX-101A, 120 kV, and 265 mA, 3.0-mm slice thickness and 0.5 pitch). In addition, all RFA procedures were performed under the guidance of CT (Philips, Brilliance-CT big core) with a 17G monopole with a 3.0 cm exposed portion (RITA-Star Burst TM/Talon XL, 1500XL; MA, USA). For tumors 3.0 cm or smaller, a single ablation was performed. For tumors larger than 3.0 cm, multiple overlapping ablation was performed. For monopolar electrode, the RFA system was activated after electrode placement within the lesion, and the electrode was gradually repositioned after ablation for each target area.

For RFA with multiple electrodes, the needle was inserted into the tumor at the site nearest to the skin. After insertion, the electrode tines were gradually unfolded. After the ablation was completed at the first site (usually 9–12 min), the electrode tines were retracted, and the cannula needle was pushed forward to the second predetermined location before the electrode tines were re-expanded for the second ablation procedure. This process was repeated until the whole target zone was adequately covered. Finally, the needle track was ablated before withdrawal of needles to prevent tumor seeding and track bleeding.

Anlotinib

Before TACE or RFA, patients received oral anlotinib (12 mg QD) from days 1 to 14 of a 21-day cycle. Treatment continued until tumor progression or discontinuation due to intolerable toxicity.

Study assessments and follow-up

Efficacy assessments

Patients were monitored for major and minor complications once a week for a total of 4 weeks. Adverse events (AEs) were defined according to Common Terminology Criteria for AEs Version 5.0, 2017. The effect of treatment on local tumor control was determined at 4–12 weeks from the start of treatment according to the modified response evaluation criteria in solid tumors (RECIST) guidelines based on the contrast-enhanced CT/magnetic resonance imaging or PET-CT. Evaluation of tumor response for extrahepatic tumors was performed using the RECIST guidelines. Time to tumor progression (TTP) was defined as the interval from the start of first treatment to the disease progression. The disease progression was recorded when the short axis of the target lesions increased by 20% or more to the baseline or if any new intrahepatic or extrahepatic lesions were detected. The overall survival (OS) time was calculated from the day when treatment was started until the date of death or the last follow-up.

Statistical methods

TTP and OS were calculated using the Kaplan–Meier method with the depicted survival curves. A two-tailed P < 0.05 was considered to be statistically significant. The Statistical Package for the Social Sciences Program was used for all analyses (SPSS, version 22.0, SPSS Inc., Chicago, IL, USA).


 > Results Top


Patient characteristics

This retrospective study enrolled 28 HCC patients with PVTT including nine female patients (32.1%) and 19 male patients (67.9%); among whom, 22 (78.6%) got ECOG-PS with 1 score. In addition, 26 (92.9%) patients suffered from hepatitis B virus, while two were infected with hepatitis C virus. Eleven (39.3%) patients had modest hepatic function in Child–Pugh B class and seven cases presented with ascites. Regarding tumor character, 16/28 (57.1%) had lesions >5 in diameter and three or more in the count of lesions. Twenty-two patients (78.6%) of the patients' blood serum AFP level was more than 400 ug/ml and 17 (60.7%) had extrahetpatic metastasis. Ina addition, 8 patients (28.6%) had Vp2 PVTT type, 17 (60.7%) had Vp3, and 3 (10.7%) had Vp4. All the patients were described as Barcelona Clinic Liver Cancer (BCLC) Stage C. Patients' baseline characteristics are shown in [Table 1].
Table 1: Baseline characteristics of patients

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All the 28 patients received 75 times of TACE (range: 1–4, 2 in median and 2.7 in mean), 88 received times of RFA (range: 1–6, 3 in median and 3.1 in mean), and 289 cycles of anlotinib (range: 2–21, 9 in median and 10.3 in mean).

Some of the extrahepatic metastasis was treated with RFA (three times for pulmonary in three patients, two times for bone in the two patients, and one time for abdominal wall in one patient). The other metastasis and intrahepatic recurrence were treated with anlotinib.

Adverse events

As shown in [Table 2], the common AEs after TACE and RFA were fever (35.7% and 71.4%), pain (42.9% and 42.9%), and fatigue (35.7% and 17.9%). The most common toxicities related to anlotinib were pharyngalgia (53.6%), fatigue (42.9%), and hand–foot skin reaction (HFSR; 39.3%), most of which were Grade 1 or 2. These clinical symptoms could be relieved during the 1st week by appropriate treatment. Moreover, Grade 3 drug-related AE (HFSR and pharyngalgia) were reported in four patients (14.3%). Grade 4 AEs were not observed.
Table 2: Incidence of treatment-related adverse events after transarterial chemoembolization/radiofrequency ablation/anlotinib treatment

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Time to tumor progression and survival time

During the median follow-up period of 13 months (range 3.4–19 months), five patients died (four patients died due to tumor progression and one died of acute heart disease). The median OS was 13 months (range 3–18 months) with 1-year OS rate of 64.3%. The median TTP was 7 months (range 1–12 months) with 6-month rates of 46.4%. According to the mRESIST1.1 criteria, two patients (7.1%) had a complete response (CR), eight patients (28.6%) had a partial response (PR), 11 patients (39.3%) had Stable disease (SD), and 7 patients (25.0%) had progressive disease (PD). The disease control rate was 82.2%. The responses of PVTT were classified as CR, PR, SD, and PD in 1, 7, 16, and 4 patients, respectively [Figure 2], [Figure 3], [Figure 4].
Figure 2: The bar graph showed the time to tumor progression and overall survival time for each patient

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Figure 3: The time curve of time to tumor progression

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Figure 4: The overall survival time curve

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 > Discussion Top


PVTT commonly occurs in 10%–40% of patients with HCC.[1],[15] These patients usually present with an advanced stage of disease and have poor prognosis;[1] the median OS in these patients is 2.7–4.0 months.[16] Sorafenib is currently considered the only evidence-based therapeutic option for patients with HCC and PVTT. Sorafenib has been recommended by the BCLC, American Association for the Study of Liver Diseases, and European guidelines.[17] However, studies have suggested that sorafenib might improve the median OS period for only 3.1–6.0 months.[16],[17] In addition, it is associated with poor tolerability and drug discontinuation, and dose reduction is often required due to AE such as diarrhea, fatigue, and HFSR.[18] Therefore, ongoing research aims to identify alternative treatments that may improve OS and maintain good compliance. Although various treatment modalities have already been tested including surgery, TACE, radiotherapy, arterial or systemic infusion of chemotherapeutic agents, and interferon therapy, no established standard therapeutic options have been developed for these patients.

Anlotinib has been used in China as a single drug therapy for patients with locally advanced or metastatic NSCLC, since it has been shown to improve both progression-free survival and OS in a Phase III trial.[12],[13],[19] Previous in vitro studies have suggested that the drug is effective for HCC; it inhibits cell proliferation and induces the apoptosis by inhibiting the activation of vascular endothelial growth factor receptor 2 and the expression of Bcl-2. It can also upregulate Bax expression by inhibiting Erk and Akt signaling transduction pathways.[13] The vascular endothelial growth factor play a pivotal role in both PVTT onset and evolution,[20] so anlotinib might control the PVTT by inhibiting the revascularization. However, so far, no studies have reported the use of anlotinib in HCC patients with PVTT.

TACE occludes the hepatic arteries, which decreases the blood flow into the target lesions. This reduced blood flow is critical in increasing the efficacy of RFA, which has been shown to be diminished by the cooling effect (called heat sink) of blood flowing into the tumor. Second, the polyvinyl alcohol granule particles infused during TACE either block or reduce the blood flow generated by tumor-induced arterioportal communications. The combination TACE and RFA generates sufficient ablative margins without radical resection. This reduces the risk of local tumor progression and recurrence by eliminating adjacent and latent micrometastasis. TACE can control the major lesions in rich blood supply, and RFA then reduces the microlesions contributing to recurrence after thermal damage.[5],[6],[7],[8],[21] Clinical evidence suggests that TACE and RFA could be used to treat advanced HCC including the patients with PVTT.[21],[22] In this study, we evaluated and compared the safety and efficacy of anlotinib, followed by TACE and RFA for the treatment of patients with HCC and PVTT. The obtained results showed a trend toward a low incidence rate of Grade 3/4 AEs for anlotinib. The previous study reported that the main Grade 3/4 AEs in HCC patients were hypertension, HFSR, and fatigue,[23] while in this study, the pharyngalgia was the most common AE, which suggested higher safety and tolerance when using anlotinib.[23] In addition, better quality of life was seen in the procession of treatment. In the SARAH trial, the rate of discontinuation of sorafenib due to drug-related toxicity reached 64%, while none of the included patients discontinued the drug for the intolerable toxicity.[24] Therefore, anlotinib may be associated with better safety target agent and could reduce the performance of TACE and RFA.

In this study, we found a median TTP and OS of 7 and 13 months, respectively, which suggested better outcome compared to HCC patients using sorafenib (only 5 of 150 patients [3.3%] achieved a PR with the median survival of 6.5 months).[25] Our data also indicated that earlier treatment of anlotinib was associated with longer TTP and OS time [Figure 2]. The advanced HCC with PVTT has a high risk of intrahepatic spread and distant metastasis.[26] TACE can produce antitumor effects by arterial obstruction, while RFA can induce tumor necrosis, thereby decreasing the risk of hepatic lesion progress regardless of PVTT. Moreover, RFA can control the extrahepatic metastasis. Anlotinib induces HCC apoptosis and inhibits proliferation of PVTT, which provides footstone for further treatment such as TACE and RFA, resulting in a longer TTP and OS.


 > Conclusion Top


To sum up, anlotinib followed by TACE and RFA is a safe and effective initial treatment approach for HCC patients with PVTT. The combination of anlotinib and TACE/RFA may be a promising therapeutic option for relieving and/or stabilizing PVTT; however, due to low sample size, further studies are necessary to confirm the presented findings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Zhao M, Wang JP, Pan CC, Li W, Huang ZL, Zhang L, et al. CT-guided radiofrequency ablation after with transarterial chemoembolization in treating unresectable hepatocellular carcinoma with long overall survival improvement. Eur J Radiol 2012;81:2717-25.  Back to cited text no. 14
    
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