Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Conductivity Rise During Irreversible Electroporation: True Permeabilization or Heat?

Purpose: Irreversible electroporation (IRE) induces apoptosis with high-voltage electric pulses. Although the working mechanism is non-thermal, development of secondary Joule heating occurs. This study investigated whether the observed conductivity rise during IRE is caused by increased cellular permeabilization or heat development. Methods: IRE was performed in a gelatin tissue phantom, in potato tubers, and in 30 patients with unresectable colorectal liver metastases (CRLM). Continuous versus sequential pulsing protocols (10-90 vs. 10-30-30-30) were assessed. Temperature was measured using fiber-optic probes. After temperature had returned to baseline, 100 additional pulses were delivered. The primary technique efficacy of the treated CRLM was compared to the periprocedural current rise. Seven patients received ten additional pulses after a 10-min cool-down period. Results: Temperature and current rise was higher for the continuous pulsing protocol (medians, gel: 13.05 vs. 9.55 °C and 9 amperes (A) vs. 7A; potato: 12.70 vs. 10.53 °C and 6.0A vs. 6.5A). After cooling-down, current returned to baseline in the gel phantom and near baseline values (Δ2A with continuous- and Δ5A with sequential pulsing) in the potato tubers. The current declined after cooling-down in all seven patients with CRLM, although baseline values were not reached. There was a positive correlation between current rise and primary technique efficacy (p = 0.02); however, the previously reported current increase threshold of 12–15A was reached in 13%. Conclusion: The observed conductivity rise during IRE is caused by both cellular permeabilization and heat development. Although a correlation between current rise and efficacy exists, the current increase threshold seems unfeasible for CRLM

Cytoskeletal Remodeling and Gap Junction Translocation Mediates Blood–Brain Barrier Disruption by Non-invasive Low-Voltage Pulsed Electric Fields

High-voltage pulsed electric fields (HV-PEF) delivered with invasive needle electrodes for electroporation applications is known to induce off-target blood–brain barrier (BBB) disruption. In this study, we sought to determine the feasibility of minimally invasive PEF application to produce BBB disruption in rat brain and identify the putative mechanisms mediating the effect. We observed dose-dependent presence of Evans Blue (EB) dye in rat brain when PEF were delivered with a skull mounted electrode used for neurostimulation application. Maximum region of dye uptake was observed while using 1500 V, 100 pulses, 100 µs and 10 Hz. Results of computational models suggested that the region of BBB disruption was occurring at thresholds of 63 V/cm or higher; well below intensity levels for electroporation. In vitro experiments recapitulating this effect with human umbilical vein endothelial cells (HUVEC) demonstrated cellular alterations that underlie BBB manifests at low-voltage high-pulse conditions without affecting cell viability or proliferation. Morphological changes in HUVECs due to PEF were accompanied by disruption of actin cytoskeleton, loss of tight junction protein—ZO-1 and VE-Cadherin at cell junctions and partial translocation into the cytoplasm. Uptake of propidium iodide (PI) in PEF treated conditions is less than 1% and 2.5% of total number of cells in high voltage (HV) and low-voltage (LV) groups, respectively, implying that BBB disruption to be independent of electroporation under these conditions. 3-D microfabricated blood vessel permeability was found to increase significantly following PEF treatment and confirmed with correlative cytoskeletal changes and loss of tight junction proteins. Finally, we show that the rat brain model can be scaled to human brains with a similar effect on BBB disruption characterized by electric field strength (EFS) threshold and using a combination of two bilateral HD electrode configurations

MWA Versus RFA for Perivascular and Peribiliary CRLM: A Retrospective Patient- and Lesion-Based Analysis of Two Historical Cohorts

PURPOSE: To retrospectively analyse the safety and efficacy of radiofrequency ablation (RFA) versus microwave ablation (MWA) in the treatment of unresectable colorectal liver metastases (CRLM) in proximity to large vessels and/or major bile ducts. METHOD AND MATERIALS: A database search was performed to include patients with unresectable histologically proven and/or (18)F–FDG–PET avid CRLM who were treated with RFA or MWA between January 2001 and September 2014 in a single centre. All lesions that were considered to have a peribiliary and/or perivascular location were included. Univariate logistic regression analysis was performed to assess the distribution of patient, tumour and procedure characteristics. Multivariate logistic regression was used to correct for potential confounders. RESULTS: Two hundred and forty-three patients with 774 unresectable CRLM were ablated. One hundred and twenty-two patients (78 males; 44 females) had at least one perivascular or peribiliary lesion (n = 199). Primary efficacy rate of RFA was superior to MWA after 3 and 12 months of follow-up (P = 0.010 and P = 0.022); however, after multivariate analysis this difference was non-significant at 12 months (P = 0.078) and vanished after repeat ablations (P = 0.39). More CTCAE grade III complications occurred after MWA versus RFA (18.8 vs. 7.9 %; P = 0.094); biliary complications were especially common after peribiliary MWA (P = 0.002). CONCLUSION: For perivascular CRLM, RFA and MWA are both safe treatment options that appear equally effective. For peribiliary CRLM, MWA has a higher complication rate than RFA, with similar efficacy. Based on these results, it is advised to use RFA for lesions in the proximity of major bile ducts

Percutaneous Liver Tumour Ablation: Image Guidance, Endpoint Assessment, and Quality Control

Liver tumour ablation nowadays represents a routine treatment option for patients with primary and secondary liver tumours. Radiofrequency ablation and microwave ablation are the most widely adopted methods, although novel techniques, such as irreversible electroporation, are quickly working their way up. The percutaneous approach is rapidly gaining popularity because of its minimally invasive character, low complication rate, good efficacy rate, and repeatability. However, matched to partial hepatectomy and open ablations, the issue of ablation site recurrences remains unresolved and necessitates further improvement. For percutaneous liver tumour ablation, several real-time imaging modalities are available to improve tumour visibility, detect surrounding critical structures, guide applicators, monitor treatment effect, and, if necessary, adapt or repeat energy delivery. Known predictors for success are tumour size, location, lesion conspicuity, tumour-free margin, and operator experience. The implementation of reliable endpoints to assess treatment efficacy allows for completion-procedures, either within the same session or within a couple of weeks after the procedure. Although the effect on overall survival may be trivial, (local) progression-free survival will indisputably improve with the implementation of reliable endpoints. This article reviews the available needle navigation techniques, evaluates potential treatment endpoints, and proposes an algorithm for quality control after the procedure

Irreversible electroporation of locally advanced pancreatic cancer transiently alleviates immune suppression and creates a window for antitumor T cell activation

Purpose: Local tumor ablation through irreversible electroporation (IRE) may offer a novel therapeutic option for locally advanced pancreatic cancer (LAPC). It may also serve as a means of in vivo vaccination. To obtain evidence of the induction of systemic antitumor immunity following local IRE-mediated ablation, we performed an explorative immune monitoring study. Methods: In ten patients enrolled in a clinical trial exploring the safety, feasibility, and efficacy of percutaneous image-guided IRE in LAPC, we determined the frequency and activation state of lymphocytic and myeloid subsets in pre- and post-treatment peripheral blood samples using flow cytometry. Tumor-specific systemic T cell responses to the pancreatic cancer associated antigen Wilms Tumor (WT)1 were determined after in vitro stimulation in an interferon-y enzyme-linked immunospot assay (Elispot), at baseline and at 2 weeks and 3 months after IRE. Results: Our data showed a transient decrease in systemic regulatory T cells (Treg) and a simultaneous transient increase in activated PD-1+ T cells, consistent with the temporary reduction of tumor-related immune suppression after the IRE procedure. Accordingly, we found post-IRE boosting of a pre-existing WT1 specific T cell response in two out of three patients as well as the de novo induction of these responses in another two patients. There was a trend for these WT1 T cell responses to be related to longer overall survival (p = .055). Conclusions: These findings are consistent with a systemic and tumor-specific immune stimulatory effect of IRE and support the combination of percutaneous IRE with therapeutic immune modulation

MR and CT imaging characteristics and ablation zone volumetry of locally advanced pancreatic cancer treated with irreversible electroporation

OBJECTIVES: To assess specific imaging characteristics after irreversible electroporation (IRE) for locally advanced pancreatic carcinoma (LAPC) with contrast-enhanced (ce)MRI and ceCT, and to explore the correlation of these characteristics with the development of recurrence. METHODS: Qualitative and quantitative analyses of imaging data were performed on 25 patients treated with percutaneous IRE for LAPC. Imaging characteristics of the ablation zone on ceCT and ceMRI were assessed over a 6-month follow-up period. Contrast ratio scores between pre- and post-treatment were compared. To detect early imaging markers for treatment failure, attenuation characteristics at 6 weeks were linked to the area of recurrence within 6 months. RESULTS: Post-IRE, diffusion-weighted imaging (DWI)-b800 signal intensities decreased in all cases (p < 0.05). Both ceMRI and ceCT revealed absent or decreased contrast enhancement, with a hyperintense rim on ceMRI. Ablation zone volume increase was noted on both modalities in the first 6 weeks, followed by a decrease (p < 0.05). In the patients developing tumour recurrence (5/25), a focal DWI-b800 hyperintense spot at 6 weeks predated unequivocal recurrence on CT. CONCLUSION: The most remarkable signal alterations after pancreatic IRE were shown by DWI-b800 and ceMRI. These early imaging characteristics may be useful to establish technical success and predict treatment outcome. KEY POINTS: • This study describes imaging characteristics after irreversible electroporation (IRE) for pancreatic adenocarcinoma. • Familiarity with typical post-IRE imaging characteristics helps to interpret ablation zones. • Post-IRE, no central and variable rim enhancement are visible on contrast-enhanced imaging. • DWI-b800 may prove useful to predict early tumour recurrence. • Post-IRE examinations reveal an initial volume increase followed by a decrease

Irreversible Electroporation for Colorectal Liver Metastases

Image-guided tumor ablation techniques have significantly broadened the treatment possibilities for primary and secondary hepatic malignancies. A new ablation technique, irreversible electroporation (IRE), was recently added to the treatment armamentarium. As opposed to thermal ablation, cell death with IRE is primarily induced using electrical energy: electrical pulses disrupt the cellular membrane integrity, resulting in cell death while sparing the extracellular matrix of sensitive structures such as the bile ducts, blood vessels, and bowel wall. The preservation of these structures makes IRE attractive for colorectal liver metastases (CRLM) that are unsuitable for resection and thermal ablation owing to their anatomical location. This review discusses different technical and practical issues of IRE for CRLM: the indications, patient preparations, procedural steps, and different "tricks of the trade" used to improve safety and efficacy of IRE. Imaging characteristics and early efficacy results are presented. Much is still unknown about the exact mechanism of cell death and about factors playing a crucial role in the extent of cell death. At this time, IRE for CRLM should only be reserved for small tumors that are truly unsuitable for resection or thermal ablation because of abutment of the portal triad or the venous pedicle