Electrochemotherapy as a New Modality in Interventional Oncology: A Review

Electroporation is a well-known phenomenon that occurs at the cell membrane when cells are exposed to high-intensity electric pulses. Depending on electric pulse amplitude and number of pulses, applied electroporation can be reversible with membrane permeability recovery or irreversible. Reversible electroporation is used to introduce drugs or genetic material into the cell without affecting cell viability. Electrochemotherapy refers to a combined treatment: electroporation and drug injection to enhance its cytotoxic effect up to 1000-fold for bleomycin. Since several years, electrochemotherapy is gaining popularity as minimally invasive oncologic treatment. The adoption of electrochemotherapy procedure in interventional oncology poses several unsolved questions, since suitable tumor histology and size as well as therapeutic efficacy still needs to be deepen. Electrochemotherapy is usually applied in palliative settings for the treatment of patients with unresectable tumors to relieve pain and ameliorate quality of life. In most cases, it is used in the treatment of advanced stages of neoplasia when radical surgical treatment is not possible (eg, due to lesion location, size, and/or number). Further, electrochemotherapy allows treating tumor nodules in the proximity of important structures like vessels and nerves as the treatment does not involve tissue heating. Overall, the safety profile of electrochemotherapy is favorable. Most of the observed adverse events are local and transient, moderate local pain, erythema, edema, and muscle contractions during electroporation. The aim of this article is to review the recent published clinical experiences of electrochemotherapy use in deep-seated tumors with particular focus on liver cases. The principle of electrochemotherapy as well as the application to cutaneous metastases is briefly described. A short insight in the treatment of bone metastases, unresectable pancreas cancer, and soft tissue sarcoma will be given. Preclinical and clinical studies on treatment efficacy with electrochemotherapy of hepatic lesions and safety of the procedure adopted are discussed

Navigation Systems for Treatment Planning and Execution of Percutaneous Irreversible Electroporation

The application of navigational systems has the potential to improve percutaneous interventions. The accuracy of ablation probe placement can be increased and radiation doses reduced. Two different types of systems can be distinguished, tracking systems and robotic systems. This review gives an overview of navigation devices for clinical application and summarizes first findings in the implementation of navigation in percutaneous interventions using irreversible electroporation. Because of the high number of navigation systems, this review focuses on commercially available ones

Detection of Incomplete Irreversible Electroporation (IRE) and Microwave Ablation (MWA) of Hepatocellular Carcinoma (HCC) Using Iodine Quantification in Dual Energy Computed Tomography (DECT)

Early detection of local tumor progression (LTP) after irreversible electroporation (IRE) and microwave ablation (MWA) of hepatocellular carcinoma (HCC) remains challenging. The goal of this study was to identify cases with insufficient ablation and prevent HCC recurrencies by measuring iodine uptake using dual-energy computed tomography (DECT). In 54 HCC-patients, the volumetric iodine concentration (VIC) of the central and peripheral ablation area was evaluated by DECT within 24 h after IRE or MWA. Follow-up was performed with CT and/or MRI at 6 weeks, 3, 6, 9, and 12 months, respectively. In both groups, LTP was solely detected in the peripheral area (IRE: n = 4; MWA: n = 4) and LTP patients showed significantly higher VIC values in the peripheral zone than patients without LTP (IRE: * p = 0.0005; MWA: * p = 0.000). In IRE-LTP patients, no significant difference between the VIC values of non-ablated liver tissue and the peripheral zone was detected (p = 0.155). The peripheral zones of IRE patients without LTP (* p = 0.000) and MWA patients, irrespective of the presence of LTP (LTP: * p = 0.005; without LTP: * p = 0.000), showed significantly lower VIC values than non-ablated liver parenchyma. Higher BCLC tumor stages were indicative for LTP (* p = 0.008). The study suggests that elevated iodine uptake in the peripheral ablation zone could help identify LTP after IRE and MWA of HCC

Safety margin assessment after microwave ablation of liver tumors: inter- and intrareader variability

Background. The aim of the study was to evaluate the inter- and intrareader variability of the safety margin assessment after microwave ablation of liver tumors using post-procedure computed tomography (CT) images as well as to determine the sensitivity and specificity of identification remnant tumor tissue. Patients and methods. A retrospective analysis of 58 patients who underwent microwave ablation (MWA) of primary or secondary liver malignancies (46 hepatocellular carcinoma, 9 metastases of a colorectal cancer and 3 metastases of pancreatic cancer) between September 2017 and June 2019 was conducted. Three readers estimated the minimal safety margin in millimeters using side-by-side comparison of the 1-day pre-ablation CT and 1-day postablation CT and judged whether ablation was complete or incomplete. One reader estimated the safety margin again after 6 weeks. Magnetic resonance imaging (MRI) after 6 weeks was the gold standard. Results. The intraclass correlation coefficient (ICC) for estimation of the minimal safety margin of all three readers was 0.357 (95%-confidence interval 0.194-0.522). The ICC for repeated assessment (reader 1) was 0.774 (95%-confidence interval 0.645-0.860). Sensitivity and specificity of the detection of complete tumor ablation, defined as no remnant tumor tissue in 6 weeks follow-up MRI, were 93%/82%/82% and 33%/17%/83%, respectively. Conclusions. In clinical practice, the safety margin after liver tumor ablation is often assessed using side-by-side comparison of CT images. In the study, we were able to show, that this technique has a poor reliability (ICC 0.357). From our point of view, this proves the necessity of new technical procedures for the assessment of the safety distance

Early Detection of Local Tumor Progression after Irreversible Electroporation (IRE) of a Hepatocellular Carcinoma Using Gd-EOB-DTPA-Based MR Imaging at 3T

Simple Summary Liver tumors like hepatocellular carcinoma (HCC) can be treated minimally invasive, e.g., by Irreversible Electroporation (IRE), which destroys the cancer. As it is possible that the tumor re-grows due to single tumor cells inadvertently not covered by the treatment, follow-up imaging of the liver is important for early detection of local tumor progression. As ablation leaves scarred tissue, recurrent tumor after IRE can appear vastly different than before treatment and thus can be hard to detect on MRI via classical imaging features. We here examined cases of local tumor progression after IRE of HCC and found distinct MR-imaging features helpful for the identification of re-grown viable tumor, namely T2 BLADE and diffusion weighted images (DWI) at the ablation zone border and T1 portal-venous and delayed phase post-contrast images in the center of the ablation zone. This knowledge will help in early detection and re-treatment of HCC for a prolonged survival. Abstract This single-center retrospective study was conducted to improve the early detection of local tumor progression (LTP) after irreversible electroporation (IRE) of a hepatocellular carcinoma (HCC) using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-based 3T MR imaging and to identify helpful signal characteristics by comparing 23 patients with and 60 patients without LTP. To identify the differences in the sensitivity of MRI sequences, the specificity, positive prediction value, negative prediction value (NPV) and diagnostic odds ratio were calculated. A chi-squared test, two-tailed student’s t-test and binary logistic regression model were used to detect distinct patient characteristics and variables for the prediction of LTP. LTP was mostly detected in the peripheral ablation zone (82.6%) within the first six months (87.0%). The central LTP ablation area presented more hypointensities in T1 p.v. (sensitivity: 95.0%; NPV: 90.0%) and in T1 d.p. (sensitivity: 100.0%; NPV: 100.0) while its peripheral part showed more hyperintensities in T2 BLADE (sensitivity: 95.5%; NPV: 80.0%) and in diffusion sequences (sensitivity: 90.0%). Liver cirrhosis seems to be an unfavorable prognosticator for LTP (p = 0.039). In conclusion, LTP mostly occurs in the peripheral ablation zone within six months after IRE. Despite often exhibiting atypical Gd-EOB-DTPA MR signal characteristics, T2 BLADE and diffusion sequences were helpful for their detection in the peripheral zone while T1 p.v. and T1 d.p. had the highest sensitivity in the central zone

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

Background. To compare the frequency of adverse events of thermal microwave (MWA) and radiofrequency ablation (RFA) with non-thermal irreversible electroporation (IRE) in percutaneous ablation of hepatocellular carcinoma (HCC). Patients and methods. We retrospectively analyzed 117 MWA/RFA and 47 IRE procedures (one tumor treated per procedure; 144 men and 20 women; median age, 66 years) regarding adverse events, duration of hospital and intensive care unit (ICU) stays and occurrence of a post-ablation syndrome. Complications were classified according to the Clavien & Dindo classification system. Results. 70.1% of the RFA/MWA and 63.8% of the IRE procedures were performed without complications. Grade I and II complications (any deviation from the normal postinterventional course, e.g., analgesics) occurred in 26.5% (31/117) of MWA/RFA and 34.0% (16/47) of IRE procedures. Grade III and IV (major) complications occurred in 2.6% (3/117) of MWA/RFA and 2.1% (1/47) of IRE procedures. There was no significant difference in the frequency of complications (p = 0.864), duration of hospital and ICU stay and the occurrence of a post-ablation syndrome between the two groups. Conclusions. Our results suggest that thermal (MWA and RFA) and non-thermal IRE ablation of malignant liver tumors have comparable complication rates despite the higher number of punctures and the lack of track cauterization in IRE

Safety and efficacy of transarterial chemoembolization with degradable starch microspheres (DSM-TACE) in the treatment of secondary liver malignancies

Purpose: To evaluate the safety and efficacy of degradable starch microspheres (DSM) as embolic agents in transarterial chemoembolization (TACE) in the treatment of secondary liver metastases. Methods: This was a national, multicenter observational study. Primary endpoints were safety and treatment response according to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Results: A total of 77 DSM-TACE procedures were performed in 20 patients. Minor immediate adverse events (AEs) were epigastric pain with an incidence of 45.5% (35/77), and nausea and vomiting at an incidence of 23.4% (18/77). Delayed minor AEs were epigastric pain in 13/77 (16.9%) treatments and nausea and vomiting in 10 (13.0%) treatments. No severe AEs were documented. Therapeutic efficacy of DSM-TACE procedures according to mRECIST was as follows: complete response 0/77, partial response 17/77, stable disease 33/77 and progressive disease 6/77, no data was available for 21/77 treatments. Overall, objective response was achieved in 8 of 20 patients (40.0%). Conclusion: DSM as embolic agent for TACE is safe in the treatment of liver metastases. An objective response in 40.0% of patients and disease control in 64.9% of procedures was achieved, and this should lead to further evaluation of DSM-TACE as treatment option for nonresectable liver metastases

Evaluation of Alterations to Bile Ducts and Laboratory Values During the First 3 Months After Irreversible Electroporation of Malignant Hepatic Tumors

Purpose: To assess the incidence and evolution of biliary alterations adjacent to the ablation area in patients with hepatic malignancies during the first 3 months after percutaneous irreversible electroporation (IRE) and to investigate associated changes in laboratory values. Material and Methods: Bile ducts located within a <1.0 cm radius of the ablation zone were analyzed in 45 patients by preinterventional and postinterventional MRI (1-3 days, 6 weeks, and 3 months after IRE). Moreover, levels of alkaline phosphatase (AP) and serum bilirubin (SB) were examined for evidence of bile duct injury. Biliary alterations and the presence of postinterventional-elevated laboratory levels were correlated with features of the lesions, patients, ablation procedures, and laboratory values. Results: A total of 80 bile ducts were located within a 1.0 cm radius of the ablation zone: 59 were encased, 16 were abutting and 5 were located within a radius of 0.1-1.0 cm of the ablation area. In total, 38 biliary injuries (narrowing, n=22; dilatation, n=14; biloma, n=2) were detected, 3 cases of narrowing occurred for the first time 6 weeks and 3 months after IRE, 21 alterations (dilatation: n=9; narrowing; n=10; biloma: n=2) had resolved during the first 6 weeks, 1 alteration (dilatation: n=1) had resolved by the last follow-up control. Three months after IRE, 19 patients showed elevated levels of AP, whereas SB levels were increased in 10 cases. No significant association between biliary alterations or postinterventional-elevated laboratory values and the investigated characteristics of lesions, patients, ablation procedures or laboratory values could be proven. Conclusion: Different alterations of bile ducts adjacent to an IRE ablation zone are common, of which dilatation and especially narrowing commonly represent a long-term complication after IRE. Moreover, a definite correlation between the frequently observed prolonged post-ablative elevation of AP- and SB-levels and the postinterventional biliary alterations could not be proven

Long-term survival after percutaneous irreversible electroporation of inoperable colorectal liver metastases

Background: For colorectal liver metastases (CRLM) that are not amenable to surgery or thermal ablation, irreversible electroporation (IRE) is a novel local treatment modality and additional option. Methods: This study is a retrospective long-term follow-up of patients with CRLM who underwent IRE as salvage treatment. Results: Of the 24 included patients, 18(75.0%) were male, and the median age was 57 (range: 28-75) years. The mean time elapsed from diagnosis to IRE was 37.9 +/- 37.3 months. Mean overall survival was 26.5 months after IRE (range: 2.5-69.2 months) and 58.1 months after diagnosis (range: 14.8-180.1 months). One-, three-, and five-year survival rates after initial diagnosis were 100.0%, 79.2%, and 41.2%; after IRE, the respective survival rates were 79.1%, 25.0%, and 8.3%. There were no statistically significant differences detected in survival after IRE with respect to gender, age, T- or N-stage at the time of diagnosis, size of metastases subject to IRE, number of hepatic lesions, or time elapsed between IRE and diagnosis. Conclusion: For nonresectable CRLM, long-term survival data emphasize the value of IRE as a new minimally invasive local therapeutic approach in multimodal palliative treatment, which is currently limited to systemic or regional therapies in this setting

Color coded perfusion imaging with contrast enhanced ultrasound (CEUS) for post-interventional success control following trans-arterial chemoembolization (TACE) of hepatocellular carcinoma

Aim Evaluation of an external color coded perfusion quantification software with CEUS for the post-interventional success control following TACE in patients with HCC. Material and methods 31 patients (5 females, 26 males, age range 34-82 years, mean 66.8 years) with 59 HCC lesions underwent superselective TACE using DSM Beads between 01/2015 and 06/2018. All patients underwent CEUS by an experienced examiner using a convex multifrequency probe (1-6 MHz) within 24 hours following TACE to detect residual tumor tissue. Retrospective evaluation using a perfusion quantification software regarding pE, TTP, mTT, Ri and WiAUC in the center of the lesion, the margin and surrounding liver. Results In all lesions, a post-interventional visual reduction of the tumor microvascularization was observed. Significant differences between center of the lesion vs. margin and surrounding liver were found regarding peak enhancement (867.8 +/- 2416 center vs 2028 +/- 3954 margin p< 0.005) and center 867.8 +/- 2416 vs 2824 +/- 4290 surrounding liver, p<0.0001)). However, no significant differences were found concerning Ri, WiAuC, mTT and TTP. Conclusion CEUS with color-coded perfusion imaging is a valuable supporting tool for post-interventional success control following TACE of liver lesions. Peak enhancement seems to be the most valuable parameter