Willemien van den Bos

Focal Therapy in Prostate Cancer: International Multidisciplinary Consensus on Trial Design

BACKGROUND Focal therapy has been introduced for the treatment of localised prostate cancer (PCa). To provide the necessary data for consistent assessment, all focal therapy trials should be performed according to uniform, systematic pre- and post-treatment evaluation with well-defined end points and strict inclusion and exclusion criteria. OBJECTIVE To obtain consensus on trial design for focal therapy in PCa. DESIGN, SETTING, AND PARTICIPANTS A four-staged consensus project based on a modified Delphi process was conducted in which 48 experts in focal therapy of PCa participated. According to this formal consensus-building method, participants were asked to fill out an iterative sequence of questionnaires to collect data on trial design. Subsequently, a consensus meeting was held in which 13 panellists discussed acquired data, clarified the results, and defined the conclusions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS A multidisciplinary board from oncologic centres worldwide reached consensus on patient selection, pretreatment assessment, evaluation of outcome, and follow-up. RESULTS AND LIMITATIONS Inclusion criteria for candidates in focal therapy trials are patients with prostate-specific antigen <15 ng/ml, clinical stage T1c-T2a, Gleason score 3+3 or 3+4, life expectancy of >10 yr, and any prostate volume. The optimal biopsy strategy includes transrectal ultrasound-guided biopsies to be taken between 6 mo and 12 mo after treatment. The primary objective should be focal ablation of clinically significant disease with negative biopsies at 12 mo after treatment as the primary end point. CONCLUSIONS This consensus report provides a standard for designing a feasible focal therapy trial. PATIENT SUMMARY A variety of ablative technologies have been introduced and applied in a focal manner for the treatment of prostate cancer (PCa). In this consensus report, an international panel of experts in the field of PCa determined pre- and post-treatment work-up for focal therapy research.

Irreversible electroporation: state of the art

The field of focal ablative therapy for the treatment of cancer is characterized by abundance of thermal ablative techniques that provide a minimally invasive treatment option in selected tumors. However, the unselective destruction inflicted by thermal ablation modalities can result in damage to vital structures in the vicinity of the tumor. Furthermore, the efficacy of thermal ablation intensity can be impaired due to thermal sink caused by large blood vessels in the proximity of the tumor. Irreversible electroporation (IRE) is a novel ablation modality based on the principle of electroporation or electropermeabilization, in which electric pulses are used to create nanoscale defects in the cell membrane. In theory, IRE has the potential of overcoming the aforementioned limitations of thermal ablation techniques. This review provides a description of the principle of IRE, combined with an overview of in vivo research performed to date in the liver, pancreas, kidney, and prostate.

Role of multiparametric magnetic resonance imaging (MRI) in focal therapy for prostate cancer:a Delphi consensus project

To define the role of multiparametric MRI (mpMRI) for treatment planning, guidance and follow‐up in focal therapy for prostate cancer based on a multidisciplinary Delphi consensus project.

Thermal Energy during Irreversible Electroporation and the Influence of Different Ablation Parameters

PURPOSE Irreversible electroporation (IRE) uses high-voltage electric fields to achieve cell death. Although the mechanism of IRE is mainly designated as nonthermal, development of secondary Joule heating is inevitable. The study purpose was to gain understanding of temperature development and distribution during IRE. MATERIALS AND METHODS IRE was performed in a transparent polyacrylamide gel resembling soft tissue. Mechanical effects, changes in temperature gradient, and absolute temperature changes were measured with three different optical techniques (high-speed, color Schlieren, and infrared imaging) to investigate the effect on temperature of variations in voltage, pulse length, active tip length (ATL), interelectrode distance, electrode configuration (parallel, convergent, and divergent), and sequential pulsing (pulse delivery interrupted by breaks). The total delivered energy was calculated. RESULTS A temperature gradient, starting at the tips of both electrodes and expanding toward each other, developed immediately with pulse delivery. Temperatures increased with increasing voltage (by 2.5°C-40.4°C), pulse length (by 5.3°C-9.8°C), ATL (by 5.9°C-17.6°C), and interelectrode distance (by 7.6°C-21.5°C), in accordance with higher energy delivery. Nonparallel electrode placement resulted in heterogeneous temperature distribution with the peak temperature focused in the area with the shortest interelectrode distance. Sequential pulse delivery significantly reduced the temperature increase compared with continuous pulsing (4.3°C vs 11.7°C). CONCLUSIONS Voltage, pulse length, interelectrode distance, ATL, and electrode configuration each have a strong effect on temperature development and distribution during IRE. Sequential pulsing reduces the extent and volume of thermal distribution and may prove beneficial with respect to procedural safety.

Irreversible electroporation of the porcine kidney: Temperature development and distribution.

OBJECTIVE Although tissue ablation by irreversible electroporation (IRE) has been characterized as nonthermal, the application of frequent repetitive high-intensity electric pulses has the potential of substantially heating the targeted tissue and causing thermal damage. This study evaluates the risk of possible thermal damage by measuring temperature development and distribution during IRE of porcine kidney tissue. METHODS The animal procedures were conducted following an approved Institutional Animal Ethics Committee protocol. IRE ablation was performed in 8 porcine kidneys. Of them, 4 kidneys were treated with a 3-needle configuration and the remaining 4 with a 4-needle configuration. All IRE ablations consisted of 70 pulses with a length 90 µs. The pulse frequency was set at 90 pulses/min, and the pulse intensity at 1,500 V/cm with a spacing of 15 mm between the needles. The temperature was measured internally using 4 fiber-optic temperature probes and at the surface using a thermal camera. RESULTS For the 3-needle configuration, a peak temperature of 57°C (mean = 49 ± 10°C, n = 3) was measured in the core of the ablation zone and 40°C (mean = 36 ± 3°C, n = 3) at 1cm outside of the ablation zone, from a baseline temperature of 33 ± 1°C. For the 4-needle configuration, a peak temperature of 79°C (mean = 62 ± 16°C, n = 3) was measured in the core of the ablation zone and 42°C (mean = 39 ± 3°C, n = 3) at 1cm outside of the ablation zone, from a baseline of 35 ± 1°C. The thermal camera recorded the peak surface temperatures in the center of the ablation zone, reaching 31°C and 35°C for the 3- and 4-needle configuration IRE (baseline 22°C). CONCLUSIONS The application of repetitive high-intensity electric pulses during IRE ablation in porcine kidney causes a lethal rise in temperature within the ablation zone. Temperature monitoring should be considered when performing IRE ablation near vital structures.

Prostate cancer diagnosis: the feasibility of needle-based optical coherence tomography

Abstract. The objective of this study is to demonstrate the feasibility of needle-based optical coherence tomography (OCT) and functional analysis of OCT data along the full pullback trajectory of the OCT measurement in the prostate, correlated with pathology. OCT images were recorded using a commercially available C7-XR™ OCT Intravascular Imaging System interfaced to a C7 Dragonfly™ intravascular 0.9-mm-diameter imaging probe. A computer program was constructed for automated image attenuation analysis. First, calibration of the OCT system for both the point spread function and the system roll-off was achieved by measurement of the OCT signal attenuation from an extremely weakly scattering medium (Intralipid® 0.0005 volume%). Second, the data were arranged in 31 radial wedges (pie slices) per circular segments consisting of 16 A-scans per wedge and 5 axial B-scans, resulting in an average A-scan per wedge. Third, the decay of the OCT signal is analyzed over 50 pixels (500  μm) in depth, starting from the first found maximum data point. Fourth, for visualization, the data were grouped with a corresponding color representing a specific μoct range according to their attenuation coefficient. Finally, the analyses were compared to histopathology. To ensure that each single use sterile imaging probe is comparable to the measurements of the other imaging probes, the probe-to-probe variations were analyzed by measuring attenuation coefficients of 0.03, 6.5, 11.4, 17, and 22.7 volume% Intralipid®. Experiments were repeated five times per probe for four probes. Inter- and intraprobe variation in the measured attenuation of Intralipid samples with scattering properties similar to that of the prostate was <8% of the mean values. Mean attenuation coefficients in the prostate were 3.8  mm−1 for parts of the tissue that were classified as benign (SD: 0.8  mm−1, minimum: 2.2  mm−1, maximum: 8.9  mm−1) and 4.1  mm−1 for parts of tissue that were classified as malignant (SD: 1.2  mm−1, minimum: 2.5  mm−1, maximum: 9.0  mm−1). In benign areas, the tissue looked homogeneous, whereas in malignant areas, small glandular structures were seen. However, not all areas in which a high attenuation coefficient became apparent corresponded to areas of prostate cancer. This paper describes the first in-tissue needle-based OCT imaging and three-dimensional optical attenuation analysis of prostate tissue that indicates a correlation with pathology. Fully automated attenuation coefficient analysis was performed at 1300 nm over the full pullback. Correlation with pathology was achieved by coregistration of three-dimensional (3-D) OCT attenuation maps with 3-D pathology of the prostate. This may contribute to the current challenge of prostate imaging and the rising interest in focal therapy for reduction of side effects occurring with current therapies.

The influence of a metal stent on the distribution of thermal energy during irreversible electroporation

Purpose Irreversible electroporation (IRE) uses short duration, high-voltage electrical pulses to induce cell death via nanoscale defects resulting from altered transmembrane potential. The technique is gaining interest for ablations in unresectable pancreatic and hepatobiliary cancer. Metal stents are often used for palliative biliary drainage in these patients, but are currently seen as an absolute contraindication for IRE due to the perceived risk of direct heating of the metal and its surroundings. This study investigates the thermal and tissue viability changes due to a metal stent during IRE. Methods IRE was performed in a homogeneous tissue model (polyacrylamide gel), without and with a metal stent placed perpendicular and parallel to the electrodes, delivering 90 and 270 pulses (15–35 A, 90 μsec, 1.5 cm active tip exposure, 1.5 cm interelectrode distance, 1000–1500 V/cm, 90 pulses/min), and in-vivo in a porcine liver (4 ablations). Temperature changes were measured with an infrared thermal camera and with fiber-optic probes. Tissue viability after in-vivo IRE was investigated macroscopically using 5-triphenyltetrazolium chloride (TTC) vitality staining. Results In the gel, direct stent-heating was not observed. Contrarily, the presence of a stent between the electrodes caused a higher increase in median temperature near the electrodes (23.2 vs 13.3°C [90 pulses]; p = 0.021, and 33.1 vs 24.8°C [270 pulses]; p = 0.242). In-vivo, no temperature difference was observed for ablations with and without a stent. Tissue examination showed white coagulation 1mm around the electrodes only. A rim of vital tissue remained around the stent, whereas ablation without stent resulted in complete tissue avitality. Conclusion IRE in the vicinity of a metal stent does not cause notable direct heating of the metal, but results in higher temperatures around the electrodes and remnant viable tissue. Future studies should determine for which clinical indications IRE in the presence of metal stents is safe and effective.

Salvage ablative therapy in prostate cancer: International multidisciplinary consensus on trial design

INTRODUCTION Salvage ablative therapy (SAT) has been developed as a form of localized treatment for localized recurrence of prostate cancers following radiation therapy. To better address the utility of SAT, prospective clinical trials must address the aspects of accepted standards in the initial evaluation, treatment, follow-up, and outcomes in the oncology community. We undertook this study to achieve consensus on uniform standardized trial design for SAT trials. METHODS A literature search was performed and an international multidisciplinary group of experts was identified. A questionnaire was constructed and sent out to 71 participants in 3 consecutive rounds according to the Delphi method. The project was concluded with a face-to-face meeting in which the results were reviewed and conclusions were formulated. RESULTS Patients with recurrent disease after radiation therapy were considered candidates for a SAT trial using any ablation scenario performed with cryotherapy or high-intensity focused ultrasound. It is feasible to compare different sources of energy or to compare with historical data on salvage radical prostatectomy outcomes. The primary objective should be to assess the efficacy of the treatment for negative biopsy rate at 12 months. Secondary objectives should include safety parameters and quality-of-life assessment. Exclusion criteria should include evidence of local or distant metastases. The optimal biopsy strategy is image-guided targeted biopsies. Follow-up includes multiparametric magnetic resonance imaging, prostate-specific antigen level, and quality of life for at least 5 years. CONCLUSIONS A multidisciplinary board from international experts reached consensus on trial design for SAT in prostate cancer and provides a standard for designing a feasible SAT trial.

What is still needed to make focal therapy an accepted segment of standard therapy

Purpose of review Focal therapy is gaining interest and this organ-preserving treatment is heading towards becoming an alternative for the conventional surgery and radiation. The purpose of this review is to determine what evidence is required to make focal therapy a viable option for treatment of localized prostate cancer. Recent findings There is still a lack of high-level evidence for the different focal treatment modalities. The early-stage focal therapy trials are conducted including a various selection of patients and different pretreatment assessment and follow-up, resulting in incomparable data. Recent literature shows it is paramount to extend the amount of biopsies and to alter the way of taking the biopsies with the template-assisted or image-guided approach. To date, multiparametric MRI is the most effective imaging technique in selecting patients for focal therapy. Summary Focal therapy trials are at the early stage of clinical development, with the majority still being phase I studies. To make focal therapy an accepted segment of standard therapy, it needs to proceed toward phase II and III trials. These trials should be conducted with an effective trial design, which will lead to more comparable oncological, functional and quality of life outcomes. Furthermore, it is essential to improve the localization of tumor foci in order to increase the accuracy of spatial targeting of cancer.

Focal irreversible electroporation as primary treatment for localized prostate cancer

To determine the safety, quality of life (QoL) and short‐term oncological outcomes of primary focal irreversible electroporation (IRE) for the treatment of localized prostate cancer (PCa), and to identify potential risk factors for oncological failure.