Similar complication rates for irreversible electroporation and thermal ablation in patients with hepatocellular tumors

Percutaneous ablation of HCC under imaging control in focal tumor therapy has gained in importance in recent years. Besides surgical resection and liver transplantation, ablation is one of three curative therapies for the treatment of hepatocellular carcinoma (HCC).1 Most ablation techniques are so-called thermal methods, which are based on the generation of coagulation necrosis by heat. While radiofrequency ablation (RFA) and microwave ablation (MWA) are among these thermal techniques, irreversible electroporation (IRE), along with other therapies such as electrochemotherapy (ECT), is a non-thermal method for destruction of tumor tissue.2, 3

IRE uses ultrashort but strong electric fields to create nanopores in the cell membrane, thereby disturbing the cellular homeostasis and subsequently causing cell death by apoptosis.4 IRE is not affected by the “heat-sink-effect”5, 6, 7, 8, 9 and can be applied in close proximity to temperature-sensitive structures such as bile ducts. Therefore, IRE is a useful technique in particular for central liver tumors in the vicinity of larger vessels and bile ducts.2 However, IRE has the theoretical disadvantage compared to thermal procedures that up to six electrodes have to be put in place (i.e., multiple trauma by puncture), and the puncture channel cannot be cauterized. First studies with limited number of cases have described possible complications after IRE, such as bleeding, portal vein thrombosis, infections, needle tract seeding and bile duct injuries.10, 11, 12 However, larger cohort studies and systematic meta-analysis involving more than 10,000 patients exist only for thermal ablation methods.13, 14 To the best of our knowledge, no work systematically compares so far the complication rates between the thermal methods RFA/MWA and IRE.

This study aims to identify possible differences between complication rates and the morbidity of patients following thermal and non-thermal ablation procedures in order to guide optimal therapy decisions in the future.

Hepatocellular carcinoma (HCC) is the world’s third most common cancer leading to death.20 In Germany, cancer of the liver and intrahepatic bile ducts are among the top 10 deaths from cancer.21 At the time of initial diagnosis, only 10–25% of patients represent candidates for surgery.22

Since early detection of cancer enables better prognosis and longer survival, it is recommended that people with the appropriate risk profile be screened for HCC.23 According to EASL guidelines, half-yearly ultrasound examinations should be performed in patients with cirrhosis of the liver in stages Child-A and Child-B as well as in patients in stage Child-C if they are eligible for liver transplantation. In the case of abnormalities, additional contrast-enhanced imaging should be performed.24, 25

In recent years, such observation strategies of patients with an increased risk-profile led to an earlier diagnosis of the disease and detection of HCCs at earlier stages. In addition to the higher chance of therapeutic response, early-stage patients also benefit from a broader range of different treatment options.26

Therapeutic options for hepatocellular carcinoma include surgical resection, liver transplantation, locoregional treatments, and chemotherapy. The final treatment decision depends mainly on the tumor stage, the patient performance status, and the functional liver reserve and requires a multidisciplinary approach.26

Which therapy is used in the respective case depends in particular on how far the disease has progressed at the time of diagnosis and in what condition the liver is. The patient’s age and the general state of health are also considered when choosing a treatment method.27, 28, 29 The effectiveness of the local-ablative therapy procedures could be proven in numerous studies of liver cancer up to a size of 3-5 cm. The use of local ablative procedures does not exclude subsequent surgical therapy. Furthermore, local-ablative procedures are often used to bridge waiting time until liver transplantation.

Irreversible Electroporation (IRE) is a novel, minimally invasive technique for the targeted destruction of cells by strong, locally limited electrical fields. Experience to date suggests that, in contrast to other local treatment methods, this technique explicitly targets the tumor cells. Other structures such as blood vessels and bile ducts are not permanently damaged. Potential disadvantages of the IRE are an increased risk of bleeding, due to the necessity of placing up to 6 electrodes in the liver and the lack of the possibility to cauterize the puncture channel.

Considering ongoing discussions which therapy should be used in respective patients, we have analyzed thermal ablation and irreversible electropo-ration ablation of HCC in the context of postinter-ventional morbidity.

In our patient cohort, the treatment decision was made by the local tumor board consisting of at least one certified hepatologist, oncologist, intervention radiologist and a highly qualified hepatobiliary surgeon with experiences in liver transplantation.

The incidence rates of the post-ablation syndrome vary significantly between studies. For example, in a prospective study of 54 patients treated with microwave ablation in liver tumors, 60% developed post-ablation syndrome.30 All in all, post-ablation syndrome is seen in about one-third of patients after thermal ablation18, 31. In our study, 17% of the patients had a post-ablation syndrome during the post-interventional clinical course with no differences between thermal and non-thermal ablations.

In this retrospective analysis, we report a systematical comparison between the complication rates of thermal ablation and IRE for a large patient collective.

Livraghi et al. reported six deaths (0.3%) and 50 other serious complications (2.2%) in a multicenter study in which more than 3,500 liver tumors were treated in 2,320 patients by thermal ablation.32 Frühling et al. reported in a single-center study a minor complication rate of 20% (6 out of 30) and one (3.3%) major complication (bile duct dilatation and stricture of the portal vein and bile duct) for IRE33, while Zeng et al. reports an event rate of 71.4% of minor and 7.1% of major complications for a small patient collective (n = 14).34

Comparing our results to previous studies we report a comparable rate of major complications (Grade III-V) for each procedure. However, numbers of minor complications (Grade I and II) are higher compared to previously reported studies. Of note, we used the “Classification of Surgical Complications” according to Clavien & Dindo”.16 In comparison to the standardized grading system of the Society of Interventional Radiology (SIR)19, 35, this classification scheme offers a more detailed insight into the grade of recorded complications and especially includes events as Grade I complications that are not included in the SIR-classification. The SIR-classification only differentiates between major and minor complications; however, the classification reported in this study distinguishes five grades of complications, ranging from minor variation from the normal postinterventional course to the death of a patient.

Despite the retrospective collection of data, we were able to demonstrate that there was no significant difference in the occurrence as well as the grade of complications regarding the use of thermal versus non-thermal ablation, indicating a noninferiority of IRE in comparison to thermal ablation techniques. This is all the more remarkable because the tumors treated with IRE were significantly more frequently close to a major vessel and thus more complication-prone. In contrast, the tumors treated with RFA/MWA were significantly more frequently located in the easily accessible periphery.

We propose that the fear of a higher complication rate should not interfere with the treatment decision regarding thermal versus non-thermal ablation.