TACE for HCC: A critical review of the 2021 CIRSE recommendations with presentation of a technique for a degradable starch microsphere—TACE

There is no consensus on which substances and which method should be used for transarterial chemoembolization. A publication commissioned by CIRSE 2021 attempted to formulate recommendations. However, only the spectrum of currently implemented procedures is outlined but no recommendation was made. In this article, therefore, basic considerations regarding the technique of chemoembolization are presented, and the authors discuss fundamental considerations about the embolic materials used, the cytostatic drugs and their dosage, as well as about pain therapy during treatment. Then, a technique is presented which used degradable starch microspheres as an embolic agent. This technique enables multiple treatments over a longer period. However, this proposal is not only evidence‐based but also eminence‐based. What we need are controlled studies that systematically compare different treatment techniques in a sufficient number of patients. This will hopefully help to find the best method for individual patients. Until then, the technique proposed by the authors can be applied.


| What should be the effect of an embolic agent?
An embolic agent basically has two different purposes (1) When mixed with the chemotherapeutic agent, it should ensure that the latter is not immediately flushed out of the liver with the bloodstream. During the period of blood stasis in the treated vascular region, the chemotherapeutic agent must remain there for a significant period (based upon the premise that tumour cells draw their supply mostly from the arteries. 9 ) (2) The embolization-dependent ischaemia phase should last long enough to affect the tumour cells.

| What further characteristics should an embolic agent have?
The regional treatment of HCCs usually requires multiple (sequential) rounds of treatment. 8 If a permanent embolic agent is used, only collateral arteries can be used for any further necessary treatment. These collateral arteries are, however, often small and only reach parts of the tumour. During a subsequent chemoembolization it is therefore often not possible to administer a therapeutic dose. A temporary embolic agent that restores blood flow after about 1-2 h in the treated section of the vessel would, therefore, be of great benefit. The particles should not be so large that they block the segmental arteries, because that would cause the collaterals in the liver to open and no ischaemia to occur. If the embolic agent is so small that it only occludes the vessels at the capillary level, two scenarios are possible: there are often small A-V fistulas in the tumour, which means there is a risk of an increased number of substances entering the circulation. It is also possible for such small particles to induce excessive necrosis with, for example the formation of an abscess. Taking the above into consideration, the ideal embolic agent should occlude the vessels at the precapillary

Key points
• Transarterial chemoembolization (TACE): There is no standard for the regional treatment of malignant tumours of the liver. We took an article from 2021 (CIRSE recommendations) as an opportunity to take up the topic in principle and to make suggestions on how best to proceed until valid studies are finally available that will help us to provide patients with the best possible treatment.
• TACE technique: Fundamental considerations about the embolic materials used, the cytostatic drugs and their dosage are discussed.
• Postembolization syndrome: the best possible treatment is discussed.
level. Capillaries have a diameter of 5-10 μm, therefore a size of about 50 μm is desirable.

| Avoiding damage to the residual liver tissue
Since it is generally not possible to apply TACE with absolute precision, a degradable embolic substance should be used to minimise damage to the surrounding liver tissue, particularly considering that in a prospective study 10 an advantage for a permanent embolic agent could not be found.
Which substances are most applicable based upon these considerations?
Temporary embolic agents should be used as a preference.
In 2018, Ebert wrote an overview of the currently used embolic agents. 11 According to this, there are only two substances that close vessels temporarily: Gelatine (Gelfoam®) and 'DSM'. Lipiodol® can also be considered as a temporary embolic agent (but it is not approved for such use).
Although Lipiodol® has been used for many years, it is still not clear how best to administer it and what effect it has. Some of the publications on the use of Lipiodol® have considerable methodological weaknesses. 1,[12][13][14] So, it would be worth discussing how Lipiodol® is to be administered: it can either be injected alone (sequentially small amounts next to the chemoembolic agent) or mixed with the chemotherapeutic agent. The Lipiodol® and the chemotherapeutic agent are mixed by connecting the two syringes filled with the substances via a three-way stopcock and then mixing the contents of the syringes by quickly emptying one of the syringes alternately. It is assumed that the frequency and speed with which the syringes are emptied influences the size of the oil droplets and their stability. 14,15 However, the size of the droplets cannot be predicted.
Lipiodol® has two undisputed marker functions: even small amounts of Lipiodol® can be recognised well under fluoroscopy (even under very unfavourable conditions, for example obese patient) and the Lipiodol® is degraded very slowly in tissues without a RES (which is true for malignant tumours) and can be detected there (with a native CT) for up to several months 16 (Figure 1). This means that, with the help of the Lipiodol®, the blood flow can be checked under fluoroscopy, and it can be ensured that there is always antegrade flow in the treated hepatic arteries.
This leaves Gelfoam™ and starch particles as temporary embolic agents.
Gelfoam® is made from pig skin. It is available as a spongy structure that can be cut into small, different-sized pieces, for example 2.5-5 mm in length, or as a powder (Gelfoam®). 4,5,17,18 The use of They were able to demonstrate that flow through the hepatic arteries was demonstrable after around 30 min. However, the findings from animal testing can only be transferred to humans to a limited extent since amylase activity in animals (particularly pigs) differs from that in humans.
There are several clinical publications on 'DSM-TACE'. In a prospective study, 23

| P OS TE MBO LIZ ATION SYNDROME
This term includes symptoms, such as pain, nausea, vomiting and fever, that occur after the treatment. The incidence of these symptoms ranges from 20% to 80%. 25,26 According to the available data, the type of embolic agent (permanent or temporary 25  to the vessel bed that is to be treated. The injection must be carried out very slowly. If it is administered too quickly, the patient feels severe pain (which, however, subsides quickly). This treatment has led to a significant reduction in the pain medication required following TACE. Undesirable side effects have not been identified with correct usage. 27 It is not known how this medication works precisely; its effectiveness may be related to the morphine receptors in the liver. 28 However, its use is off label.

| HERE IS OUR TRE ATMENT SUGG E S TION
The TACE of HCCs is always palliative. It must be repeated several An anthracycline should be used as a first choice. The first dose should not be higher than 50 mg. If this is ineffective, the dose may be increased up to 100 mg. The total dose of 700 mg/ m 2 should not be exceeded due to the risk of cardiomyopathy. The patient's cardiac function should be checked after two or three rounds of chemoembolization as a precaution. If changes are detected, switch to Cisplatin. This also becomes necessary if the tumour shows signs of progression. Neurotoxicity, nephrotoxicity, and cardiotoxicity must be expected from a cumulative dose of 400 mg/m 2 of Cisplatin. 29 The effects of anthracyclines and cisplatin in the regional treatment of HCC are probably comparable. 4 However, there are no prospective and randomised studies on this question. The reason why we use an anthracycline first and cisplatin as a second choice is due to the spectrum of side effects: Cisplatin often cause nausea or vomiting and can lead to kidney damage.
Before each chemoembolization, a bile-permeable cephalosporin (e.g., ceftriaxone) should be given once to prevent the possible infection of necrosis occurring because of the chemoembolization.
Before the treatment, the patient should be hydrated intravenously with 1000 mL physiological NaCl solution, provided the kidney function is not impaired.
Administration of an antiemetic (e.g., ondansetron 4 mg before and after chemoembolization) is usually only necessary if Cisplatin is used.
During treatment, the patient should be sedated, for example with a mixture of 100 mg pethidine + 1000 mg Metamizole and 10 mg of Midazolam diluted in 500 mL of physiologic NaCl intravenously.
Oxygen saturation and blood pressure are monitored continuously.
The artery supplying the tumour should be cannulated selectively. If several tumours located in different parts of the liver need to be treated, the respective arteries must be probed individually.
Depending on the patient's condition and liver function, treatment can also be spread across two separate sessions.
Diagnostic angiography must be performed prior to any chemoembolization. In addition to identifying the arteries supplying the tumour(s), larger A-V shunts must be ruled out. If such a shunt is discovered, it must be embolized. Atypical vessels that may arise from the aorta, from the inferior phrenic artery or from other regional arteries must be identified. When blood flow is slow, for example only 3 mL of the amilomer liquid should be used, the cytostatic must dissolved in it and then diluted again with 12 mL of physiological saline solution. The resulting 15 mL liquid can then be injected slowly.
The starch particles, which are heavier than water, sediment very quickly. It, therefore, is necessary to stir the mixture thoroughly before filling the next syringe with the 'Anthracycline-EmboCept®S' mixture.
In addition to the mixture consisting of the chemotherapeutic drug and EmboCept®S, Lipiodol® is injected at regular intervals. The chemoembolizate is injected until there is a significant slowdown of the blood flow in the treated arteries or when 50 mg of the chemotherapy drug has been injected. It is not necessary to increase the dose up until the point of complete blood stasis. There is a high risk that blood stasis in the treated arteries will damage the vessel wall. It is absolutely necessary to protect the arteries of the liver as much as possible, for the subsequent treatments.
F I G U R E 2 Treatment situation: two insulin syringes are connected via a three-way stopcock: either the chemoembolizate or the Lipiodol® is injected by turning the stopcock.
A non-enhanced CT scan of the liver is performed on the day after chemoembolization. The Lipiodol®, which is detected on these CT scans, must be inside the tumour and it can be determined whether the tumour area has been adequately reached by the treatment. Such a CT is also necessary if another artery had to be probed during the course of treatment.
Most contributors agree that chemoembolization must be repeated regularly in patients with HCC. The necessary frequency and the necessary intervals between the individual sessions have not yet been the subject of controlled studies. The authors used the following scheme: 'initial therapy' and 'maintenance therapy'. 'Initial therapy' consists of the first three sessions of treatment, which are carried out at intervals of between two and a maximum of 4 weeks (depending on the patient's condition and liver function). This is followed by 'maintenance therapy', which is carried out twice a year if no tumour growth can be detected. Restaging is performed before every 'maintenance therapy'. If restaging shows renewed tumour growth, an 'initial therapy cycle' is repeated. However, every patient should be seen by the general practitioner at least every 3 months.
In addition, the patient is instructed to present himself immediately if his general condition changes.

| CON CLUS ION
According to the actual ESM0 Committee Guidelines, 30 liver chemoembolization is the preferred method for treating inoperable HCC.
Although it has been carried out for many years, there is no treatment regimen that has been validated by prospective studies and is generally accepted as a standard procedure. In our opinion, it is of greatest importance how the treatment is performed, that is which substances in what mixture and sequences are used and how often the treatment is repeated. All previously known studies were carried out using different techniques and different substances. They do not allow a valid comparison of different studies. We present an easy-to-perform TACE technique using DSM as the embolic agent and Lipiodol® as the marker substance that is easy to perform, can be repeated often, and is very well tolerated by patients.
As long as there are no prospective studies in which, for example different mixtures of substances and time sequences are examined, our recommendation is to employ our proposed treatment scheme.
There is an urgent need to establish a scientifically based treatment for patients with HCC. We appeal to all who have the necessary resources and are interested in making progress, to implement randomised and controlled studies with a sufficient number of patients.

AUTH O R CO NTR I B UTI O N S
The two authors have seen and agreed with the contents of the manuscript. All the authors contributed to the compilation and analysis of the data and the preparation of the manuscript.

FU N D I N G I N FO R M ATI O N
This work was not supported by any funding.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that they have no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data derived from public domain resources.