Chinese expert consensus on technical recommendations for the standard operation of drug-eluting beads for transvascular embolization.

Liver cancer is among the 10 most common tumors globally. In China, liver cancer ranks 4th for prevalence and 3rd for mortality among all malignant tumors. With respect to the treatment of primary liver cancer, there are a number of therapies currently available, including surgical resection, liver transplantation, ablation, transarterial chemoembolization (TACE), systemic chemotherapy, radiation therapy, targeted drug therapy and immunotherapy. Clinical practice and research have shown that, compared with conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE) can achieve a higher response rate and longer survival time in patients with primary liver cancer. Compared with that of cTACE, DEB-TACE has more favorable basic conditions for achieving uniformity, which could facilitate the standardization of operation techniques. China is the country with the highest incidence of primary liver cancer, accounting for more than 50% of the global patients, and its etiology and epidemiology in Chinese patients differ from those in Europeans and Americans. Therefore, experts in China have drafted these technical recommendations for the standard operation of drug-eluting beads for the treatment of liver cancer on the basis of accumulated abundant clinical experience and evidence-based medical data. 2021 Annals of Translational Medicine. All rights reserved.

Introduction

Primary liver cancer is one of the most common malignant tumors, ranking 6th and 4th of all cancers for global incidence and mortality, respectively (1,2). China is a high-incidence country for primary liver cancer. According to Cancer statistics in China, 2015, among malignant tumors in the Chinese population, liver cancer ranked 4th for incidence and had the third highest fatality rate. In 2010, the China Anti-Cancer Association carried out a survey on the status quo of primary liver cancer, which showed that more than 80% of patients with primary liver cancer had already progressed to intermediate or advanced stage disease at the time of diagnosis (3). With respect to the treatment of primary liver cancer, there are a number of therapies currently available, including surgical resection, liver transplantation, ablation, transarterial chemoembolization (TACE), systemic chemotherapy, radiation therapy, and targeted drug therapy. Immunotherapy has also recently been incorporated into the second-line clinical treatment options for patients with primary liver cancer. For patients with primary liver cancer with no indications for surgery, TACE has been recommended as the preferred therapy by Barcelona Clinic Liver Cancer (BCLC) guidelines.

TACE involves the selective or superselective insertion of a catheter into the artery supplying the tumor with blood, after which appropriate amounts of chemotherapeutic drugs and embolic agents are injected at an appropriate speed to block the target artery, thus killing tumor cells and inducing tumor tissue necrosis (4). The therapeutic mechanism of TACE in primary liver cancer mainly consists of two parts: the first involves the effect of chemotherapy, and the other involves the effect of embolization. The selection of the appropriate chemotherapeutic drug regimen and precise embolization is crucial to the prognosis of patients (5).

Since Llovet et al. published the results of a randomized controlled trial on TACE treatment for patients with primary liver cancer in 2002, many studies have demonstrated that this treatment can significantly improve survival of patients with liver cancer compared with conventional treatment (5-9). The therapeutic effects of TACE have been particularly noteworthy in patients with intermediate- and advanced-stage liver cancer who were not candidates for surgical resection (4,6). In recent years, various major guidelines have recommended TACE as a first-line treatment for patients with intermediate and advanced stage primary liver cancer (10,11). For instance, the BCLC guidelines recommend TACE as a first-line treatment option for patients with BCLC-B hepatocellular carcinoma (HCC). The Guidelines for the Diagnosis and Treatment of Primary Liver Cancer in China (2017 edition) adopted TACE as an alternative treatment for stage Ib to IIIb primary liver cancer; for patients with stages IIb to IIIa, TACE was also recommended as the preferred treatment (8).

Conventional TACE (cTACE) is routinely used in clinical practice. cTACE is delivered by mixing iodinated oil with chemotherapeutic drugs (such as doxorubicin) at a certain ratio to form an iodinated oil emulsion. Embolic particles (such as polyvinyl alcohol) or gelatin sponge can also be added to strengthen vascular embolism. The emulsion is then injected into the tumor blood vessels in a selective or superselective manner via a catheter (12). However, in its clinical application, cTACE has several shortcomings. First, a unified technical standard for the selection of chemotherapeutic drug regimens, embolic materials and operating methods has not been formed, and significant variations in technical details exist among treating physicians. Second, it is challenging to fully mix the lipiodol and chemotherapeutic drugs used in the emulsion in cTACE and to achieve sufficient stability. Furthermore, the chemotherapeutic drugs and lipiodol can quickly separate, causing the drugs to stay in the tumor only for a short time. Third, lipiodol cannot be deposited into some special tumors, such as metastatic liver cancer and cTACE resistant; thus, continuous embolization and chemotherapy fail to be delivered which limits the efficacy of this approach significantly (6,13,14). Indeed, adequate local concentration of chemotherapeutic drugs within lesions and the continuous treatment with chemotherapeutic drugs are closely associated with killing tumor cells.

Clinical practice has indicated that long-term deposition of lipiodol and continuous high-concentration release of chemotherapeutic drugs into the lesion are the key factors in achieving treatment efficacy (6). As such, new treatment is needed to solve the defect of lipiodol, and the drug-eluting microspheres have emerged with the development of medicine and biotechnology. The mechanism of drug-eluting microsphere drug includes absorption of positive and negative ions, which enables the slow and continuous release of chemotherapeutic drugs into the lesion as well as occlusion of tumor blood vessels by the microspheres. In 2004, British BTG plc developed and launched DC Bead, the world's first drug-eluting bead onto which doxorubicin and irinotecan can be loaded, which then quickly obtained approval from various European and American organizations for application in the treatment of primary and secondary liver cancer (15-18). In the years that followed, several drug-eluting microspheres were launched successively, including HepaSphere (19), CalliSpheres (20) and TANDEM (21). Drug-eluting microspheres come in a variety of sizes. Currently, the most commonly used particle sizes are 70–150, 100–300 and 300–500 µm. Microspheres of different particle sizes can be applied to tumors with different sizes and varying degrees of blood supply. Furthermore, drug-eluting microspheres have unique advantages in terms of drug loading, and can load and release a therapeutic dose of chemotherapeutic drugs in a continuous and slow manner. Currently, the commonly used drug-eluting microspheres on the market can be loaded with 50–75 mg of doxorubicin or 100 mg of irinotecan per bottle. The limit for epirucibinc for single session is 150 mg. The concentration of drug delivered to the tumor tissue by drug-eluting microspheres can reach 11.5 times that delivered via transarterial drug perfusion (22), with a sustained chemotherapy drug release time of 36 days. Furthermore, many studies have shown that the effective drug concentration can be detected at a distance of 600 µm from the microspheres (18,23-26). After being loaded with chemotherapeutic drugs, a drug-eluting microsphere may undergo certain changes in its diameter. DC Beads and CalliSpheres microspheres shrink to a certain degree after drug loading, whereas HepaSphere microspheres, as a swelling-type drug-loaded bead, can expand up to four times their original volume.

More than 10 years of clinical experience have been accumulated in the use of drug-eluting bead TACE (DEB-TACE) since 2004. In 2016, Facciorusso et al. summarized the published literature over the previous decade and reported that DEB-TACE can achieve a better complete response (CR) rate and longer survival time than cTACE in patients with primary liver cancer. In addition, the authors mentioned that DEB-TACE and is superior to cTACE in the aspects of hepatic injury and chemotherapeutic side effects (27). The results of a meta-analysis conducted by Zou et al. arrived at the same conclusions (4,28-32). However, analyses of survival time with these two treatments have produced inconsistent results. For instance, another study by Arabi et al. showed no difference between cTACE and DEB-TACE with respect to the survival time of patients with liver cancer (33). In 2018, DEB-TACE is considered important treatment for HCC like TACE and SIRT in the EASL Clinical Practice Guidelines (34). Despite some inconsistencies, there is no doubt that DEB-TACE, as a new type of chemotherapy and embolization technology, has become increasingly valued by clinicians for the treatment of intermediate- and advanced-stage liver cancer. In 2015, drug-eluting microspheres obtained approval in China and started to be used clinically, and to date, we have already accumulated experience using them to treat more than 50,000 patients.

Compared with that of cTACE, DEB-TACE has more favorable basic conditions for achieving uniformity, which could facilitate the standardization of operation techniques. In 2012, the European Guidelines for DEB-TACE Operation were published, and in 2018, the Expert Consensus on DEB-TACE Operation in Taiwan was published (35). China is the country with the highest incidence of primary liver cancer, accounting for more than 50% of the global patients, and its etiology and epidemiology in Chinese patients differ from those in Europeans and Americans. Therefore, it is of great significance to formulate an expert consensus and guidelines for DEB-TACE in patients with primary liver cancer in China. After soliciting opinions from tumor interventional therapy experts in China, and taking into account treatment data from more than 5,000 patients (36-39), we finally formed this China Experts Consensus on the Technical Recommendations for Standard Operation of DEB-TACE through repeated discussions, with the aim of standardizing DEB-TACE operation techniques to benefit a wider range of patients. The levels of evidence and recommendations have been evaluated by the U.S. Preventive Services Task Force (Tables S1,S2).

The indications for DEB-TACE are the same as those for cTACE. We may refer to the Chinese Clinical Practice Guidelines for Transarterial Chemoembolization (40).

DEB-TACE may also be used as a salvage treatment for patients with cTACE-resistant hepatocellular carcinoma (41).
(Level of evidence: III; pagrade of recommendation: A).

DEB-TACE may be more effective than cTACE in patients with Child-Pugh B, ECOG 1, bilobar disease, and recurrent disease (42).

Patients who have liver-only or liver-dominant metastatic disease and tumor load does not exceed 60% may be considered irinotecan-loaded drug-eluting beads (DEBIRI) (43).

Contraindications to DEB-TACE

Relative contraindications: (I) for patients with ≥70% of the tumor in the whole liver whose liver function is graded as Child-Pugh class A–B, then fractional embolization may be considered. (II) For patients with peripheral blood leukocytes <3.0×109/L and platelets <50×109/L due to hypersplenism, partial splenic arterial embolism should be performed first, followed by DEB-TACE. (III) According to Cheng’s Classification (Table S3), for patients with type II or higher portal vein tumor thrombosis whose liver function is graded as Child-Pugh class A–B, if there is collateral circulation in the portal vein, then DEB-TACE should be performed. (IV) Patients with hepatic arterioportal fistula should undergo correction by embolism before treatment with DEB-TACE.

(Level of evidence: II-1; grade of recommendation: A).

Absolute contraindications: (I) severe liver dysfunction (Child-Pugh class C liver function), including severe jaundice, hepatic encephalopathy, refractory ascites, or hepatorenal syndrome; (II) uncorrectable severe coagulation hypofunction; (III) complete embolism of the main portal vein by cancer embolus, with little collateral angiogenesis, for which the portal vein stent cannot improve the main portal vein's blood flow to the liver; (IV) complicated with active hepatitis or severe infection which cannot be treated synchronously; (V) diffuse tumor or widespread metastasis, with an expected survival duration of <3 months; (VI) Eastern Cooperative Oncology Group (ECOG) score >2 points, cachexia, or multiple organ failure; (VII) renal dysfunction, with creatinine >176.8 µmol/L or creatinine clearance rate <30 mL/min; (VIII) a significant and uncorrectable reduction in peripheral white blood cells and platelets caused by chemotherapeutic drugs or other drugs, with white blood cells <3.0×109/L, and platelets <50×109/L; (IX) severe hypersensitivity to iodinated contrast agent; (X) hepatic artery-hepatic venous fistula that cannot be corrected by embolization.

(Level of evidence: II-1; grade of recommendation: A).

Preprocedural imaging: should be assessed number, size, and location of liver lesions, imaging should be either a contrast-enhanced multiphasic CT or contrast-enhanced MRI examinations should include plain scanning in the arterial and venous phases and for what concern MRI hepatobiliary late phase.
(Level of evidence: I; grade of recommendation: A).

Laboratory examinations and clinical assessments: routine bloods, hepatic and renal function, electrolyte, coagulation function, hepatitis virus index, tumor marker and Performance Status (PS) score, Child-Pugh classification (Table S4), and BCLC classification (Table S5), with reference to the Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 edition) (8).

Perioperative medication: In general, antibiotics are not used before surgery. However, for patients undergoing bilioenteric anastomosis, who have a history of Endoscopic Retrograde Cholangiopancreatography (ERCP), sfinterotomy, intrahepatic bile duct stones, Transjugular Intrahepatic Portosystemic Shunt (TIPS), diabetes mellitus, HIV+, antibiotic therapy may be used during the perioperative period. Acid suppression, anti-emesis, and other treatments should be given 1 hour before the operation.
(Level of evidence: III; grade of recommendation: B).

Drug loading

In this consensus, we have collected the drug loading processes of three types of microspheres currently available in China, as detailed in Appendix 1.

See .

Table 1

Recommendations on the selection of particle size for drug-eluting microspheres

Particle size of microsphere	Patient group selection
70–150 μm	<5 cm (tumor size), 70–150 μm is recommended
	>5 cm (tumor size), insufficient blood supply without arteriovenous fistula
	Metastatic liver cancer
	(Level of evidence: II-2; grade of recommendation: A)
100–300 μm	>5 cm, with sufficient blood supply, 100–300 μm is recommended
	(Level of evidence: II-1; grade of recommendation: A)
300–500 μm	>7 cm, 300–500 μm is recommended for primary liver cancer with abundant blood supply
	(Level of evidence: II-2; grade of recommendation: B)

For tumors meeting the Milan standards for liver cancer (i.e., diameter of a single tumor ≤5 cm; with <3 multiple tumors and a maximum diameter ≤3 cm), 1 bottle (2×2 mL) of microspheres is recommended, and for tumors exceeding the Milan standards, up to 2 bottles (2×2 mL) of microspheres are recommended. For patients with primary liver cancer, doxorubicin is recommended as the loading drug.

For patients with metastatic liver cancer (e.g., colorectal cancer metastasis), the loading of 100 mg irinotecan is recommended.

The use of drug-eluting microspheres

Recommendations on the dosage and loading drugs of microspheres

In cases in which the tumor lesion still has a visible blood supply after the injection of drug-eluting microspheres, then other blank microspheres or gelatin sponge particles can be injected to strengthen embolism.

Recommendations on microcatheter selection

To ensure smooth operation, Different size of microsphere need appropriate microcatheter. Please refer to the Table S6.

Recommended injection speed

After the catheter has been placed, an injection speed of 1 mL/min is recommended. With respect to large tumors with abundant blood vessels, a slightly faster (2–3 mL/min) initial injection speed can be used, depending on blood flow conditions, and then slowed down. Before the injection of drugs, surgeon should ensure that microspheres are suspended properly, and the entire process of microsphere injection should be performed under X-ray monitoring.

Catheter positioning

Prior to each embolization, angiography of the hepatic should be performed to demonstrate liver arterial anatomy and feeding arteries to the tumor, as well as to check for obvious portal or venous shunts.

Radiography should be used to confirm the nourishing blood vessels of the tumor before embolism. Cases of arteriovenous fistula should first be corrected through embolization for any blood vessels that cannot be avoided (such as the gastroduodenal artery), protective embolization can be performed with spring coils.
(Level of evidence: II-2; grade of recommendation: B).

For lesions with multiple tumor-feeding blood vessels, superselective embolization should be performed on all tumor-feeding blood vessels for which it is possible. For lesions that cannot be treated with superselective embolization, embolization should be performed as close to complete embolization as possible, and important blood vessel branches such as the gallbladder artery should be avoided.

Selection of endpoint for embolization

After DEB-TACE has been performed, there are two endpoints for embolization.

Complete embolization the blood flow in tumor-feeding vessels is observed to be completely stagnated.

Approximate embolization: contrast agent retention which is cleared after 2–5 cardiac cycles.

These embolization endpoints should be confirmed by angiography again in 5 minutes later. Whether further embolization is needed should be considered based on the staining results of the tumor.

(Level of evidence: II-2; grade of recommendation: B).

Currently, the selection of complete embolization or approximate embolization needs to be determined on a case-by-case. Complete embolization is recommended as the endpoint if the microcatheter can be superselectively into the tumor-feeding artery, whereas approximate embolization is recommended, because we must reduce the complications which induced by completed embolization.

Postoperative follow-up and evaluation

Postoperative follow-up

Enhanced CT or MRI reexamination should be performed 4–6 weeks after DEB-TACE treatment, with enhanced MRI being the preferred examination method. If no remaining viable tissue are found during the imaging reexamination, follow-up imaging reexamination should be conducted every 3 months thereafter.

(Level of evidence: I; grade of recommendation level: A).

Efficacy evaluation

Reference to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) is recommended for evaluation of the therapeutic effect on lesions. Tumor response is evaluated as follows, CR: CT or MRI shows no enhancement in any of the target lesions; partial response (PR): the total diameter of the target lesions in contrast-enhanced images in the arterial phase is reduced by ≥30%; progressive disease (PD): the total diameter of the target lesions in contrast-enhanced images in the arterial phase is increased by ≥20% or new lesions are found; stable disease (SD): the total diameter of the target lesions in contrast-enhanced images in the arterial phase is between decreased by <30% and increased by <20%. For patients who fail to reach CR but meet the treatment requirements in terms of liver function, blood test results, and other conditions with no contraindications, DEB-TACE treatment may be repeated. Clinical efficacy may be evaluated according to short-term efficacy and long-term efficacy. The evaluation index for short-term efficacy is time to progression, and the evaluation index for long-term efficacy is overall survival. Neutrophil-to-lymphocyte ratios (NLR) and platelet-to-lymphocyte ratios (PLR) maybe be good marker to predict the prognosis of DEB-TACE in HCC. The article proved that high baseline NLR and PLR were predictive of poorer tumor response and shorter PFS (44).

Treatment of postoperative complications

The postoperative complications of DEB-TACE are basically similar to those of cTACE and are described below.

Post-embolization syndrome, which mainly manifests as fever, nausea, vomiting, oppressive liver pain, abdominal distension, anorexia, and other symptoms, can be treated with oxygen inhalation, anti-emesis, analgesia, acid suppression, fasting, intravenous hydration, liver protection therapy, and other therapies (4,8,17,32).
(Level of evidence: III; grade of recommendation: B).

The incidence rate of bile duct injury and ectopic hepatic embolic necrosis is higher after DEB-TACE than after cTACE. Therefore, superselection must be performed properly during the operation, and the best endpoint of embolization should be chosen. In cases of increased bilirubin, supportive therapy, such as liver protection and jaundice treatments, should be actively administered.

Liver abscess and biloma: patients with liver abscesses after surgery should be administrated with antibiotics or treated with percutaneous drainage; percutaneous drainage can also be used to treat cases of large biloma (45-47). For high-risk patients (such as those with a history of biliary surgery, antibiotics should be used prophylactically).
(Level of evidence: III; grade of recommendation: B).

For patients with ectopic embolism, the following precautions should be taken: (i) microspheres with a particle size appropriate to the tumor size and blood supply conditions should be selected. (ii) Superselection of tumor-feeding arteries should be performed in a proper manner to prevent the microspheres from entering into normal liver tissues. (iii) The speed of the microsphere injection should be controlled by 1 mL/min (48).
(Level of evidence: III; grade of recommendation: B).

Summary and outlook

With the standardization of operation techniques, the clinical application of DEB-TACE is expected to increase and further improve the efficacy of interventional therapies for liver tumors. In the meantime, the drug-loading range of microspheres is expected to be further expanded to enable the loading of immune drugs, targeted drugs, radioactive substances, and other drugs. Moreover, the research and development of luminous microspheres will increase the accuracy of microsphere embolization, thus reducing the risks of ectopic embolism and complications, and further improving the efficacy of DEB-TACE for patients with liver cancer. As we know, the treatment of liver cancer is a comprehensive treatment. In any studies, DEB-TACE combined with radiofrequency ablation or sorafenib get better effect compared with DEB-TACE alone in liver cancer (49,50). In the future, DEB-TACE combined other treatment like SIRT, immunotherapy will get better overall response rate and overall survival in HCC. It need more studies to prove.

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