Joost W. Wijlemans

Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis

PURPOSE Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases. METHODS AND MATERIALS A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated for overall pain response for reirradiation of metastatic bone pain. RESULTS Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49-0.67). There was a substantial between-study heterogeneity (I² = 63.3%, p = 0.01) because of clinical and methodological differences between studies. CONCLUSIONS Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.

Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation of liver tumours.

Abstract Recent decades have seen a paradigm shift in the treatment of liver tumours from invasive surgical procedures to minimally invasive image-guided ablation techniques. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a novel, completely non-invasive ablation technique that has the potential to change the field of liver tumour ablation. The image guidance, using MR imaging and MR temperature mapping, provides excellent planning images and real-time temperature information during the ablation procedure. However, before clinical implementation of MR-HIFU for liver tumour ablation is feasible, several organ-specific challenges have to be addressed. In this review we discuss the MR-HIFU ablation technique, the liver-specific challenges for MR-HIFU tumour ablation, and the proposed solutions for clinical translation.

A clinically feasible treatment protocol for magnetic resonance-guided high-intensity focused ultrasound ablation in the liver.

ObjectivesMagnetic resonance–guided high-intensity focused ultrasound (MR-HIFU) allows for noninvasive thermal ablation under real-time temperature imaging guidance. The purpose of this study was to assess the feasibility and safety of MR-HIFU ablation of liver tissue in a clinically acceptable setting. The experimental protocol was designed with a clinical ablation procedure of a small malignant tumor in mind; the procedures were performed within a clinically feasible time frame and care was taken to avoid adverse events. The main outcome was the size and quality of the ablated liver tissue volume on imaging and histology. Secondary outcomes were safety and treatment time. Materials and MethodsHealthy pigs (n = 10) under general anesthesia were positioned on a clinical MR-HIFU system, which consisted of an HIFU tabletop with a skin cooling system integrated into a 1.5-T MR scanner. A liver tissue volume was ablated with multiple sonication cells (4 × 4 × 10 mm, 450 W). Both MR thermometry and sonication were respiratory-gated using a pencil beam navigator on the diaphragm. Contrast-enhanced T1-weighted (CE-T1w) imaging was performed for treatment evaluation. Targeted total treatment time was 3 hours. The abdominal wall, liver, and adjacent organs were inspected postmortem for thermal damage. Ablated tissue volumes were processed for cell viability staining. The ablated volumes were analyzed using MR imaging, MR thermometry, and cell viability histology. ResultsEleven volume ablations were performed in 10 animals, resulting in a median nonperfused volume (NPV) on CE-T1w imaging of 1.6 mL (interquartile range [IQR], 0.8–2.3; range, 0.7–3.0). Cell viability histology showed a damaged volume of 1.5 mL (IQR, 1.1–1.8; range, 0.7–2.3). The NPV was confluent in 10 of the 11 cases. The ablated tissue volume on cell viability histology was confluent in all 9 available cases. In all cases, there was a good correspondence between the aspects of the NPV on CE-T1w and the ablated volume on cell viability histology. Two treatment-related adverse events occurred: 1 animal had a 7-mm skin burn and 1 animal showed evidence of thermal damage on the surface of the spleen. Median ablation time was 108 minutes (IQR, 101–120; range, 96–181 minutes) and median total treatment time was 180 minutes (IQR, 165–224; 130–250 minutes). ConclusionsOur results demonstrate the feasibility and safety of MR-HIFU ablation of liver tissue volumes. The imaging data and cell viability histology show, for the first time, that confluent ablation volumes can be achieved with motion-gated ablation and MR guidance. These results were obtained using a readily available MR-HIFU system with only minor modifications, within a clinically acceptable time frame, and with only minor adverse events. This shows that this technique is sufficiently reliable and safe to initiate a clinical trial.

Evolution of the ablation region after magnetic resonance-guided high-intensity focused ultrasound ablation in a Vx2 tumor model.

ObjectivesVolumetric magnetic resonance (MR)–guided high-intensity focused ultrasound (HIFU) is a completely noninvasive image-guided thermal ablation technique. Recently, there has been growing interest in the use of MR-HIFU for noninvasive ablation of malignant tumors. Of particular interest for noninvasive ablation of malignant tumors is reliable treatment monitoring and evaluation of response. At this point, there is limited evidence on the evolution of the ablation region after MR-HIFU treatment. The purpose of the present study was to comprehensively characterize the evolution of the ablation region after volumetric MR-HIFU ablation in a Vx2 tumor model using MR imaging, MR temperature data, and histological data. Materials and MethodsVx2 tumors in the hind limb muscle of New Zealand White rabbits (n = 30) were ablated using a clinical MR-HIFU system. Twenty-four animals were available for analyses. Magnetic resonance imaging was performed before and immediately after ablation; MR temperature mapping was performed during the ablation. The animals were distributed over 7 groups with different follow-up lengths. Depending on the group, animals were reimaged and then killed on day 0, 1, 3, 7, 14, 21, or 28 after ablation. For all time points, the size of nonperfused areas (NPAs) on contrast-enhanced T1-weighted (CE-T1-w) images was compared with lethal thermal dose areas (ie, the tissue area that received a thermal dose of 240 equivalent minutes or greater [EM] at 43°C) and with the necrotic tissue areas on histology sections. ResultsThe NPA on CE-T1-w imaging showed an increase in median size from 266 ± 148 to 392 ± 178 mm2 during the first day and to 343 ± 170 mm2 on day 3, followed by a gradual decrease to 113 ± 103 mm2 on day 28. Immediately after ablation, the NPA was 1.6 ± 1.4 times larger than the area that received a thermal dose of 240 EM or greater in all animals. The median size of the necrotic area on histology was 1.7 ± 0.4 times larger than the NPA immediately after ablation. After 7 days, the size of the NPA was in agreement with the necrotic tissue area on histology (ratio, 1.0 ± 0.2). ConclusionsDuring the first 3 days after MR-HIFU ablation, the ablation region increases in size, after which it gradually decreases in size. The NPA on CE-T1-w imaging underestimates the extent of tissue necrosis on histology in the initial few days, but after 1 week, the NPA is reliable in delineating the necrotic tissue area. The 240-EM thermal dose limit underestimates the necrotic tissue area immediately after MR-HIFU ablation. Reliable treatment evaluation techniques are particularly important for noninvasive, image-guided tumor ablation. Our results indicate that CE-T1-w imaging is reliable for MR-HIFU treatment evaluation after 1 week.

Intercostal high intensity focused ultrasound for liver ablation: The influence of beam shaping on sonication efficacy and near-field risks

PURPOSE One of the major issues in high intensity focused ultrasound ablation of abdominal lesions is obstruction of the ultrasound beam by the thoracic cage. Beam shaping strategies have been shown by several authors to increase focal point intensity while limiting rib exposure. However, as rib obstruction leaves only part of the aperture available for energy transmission, conserving total emitted acoustic power, the intensity in the near-field tissues inherently increases after beam shaping. Despite of effective rib sparing, those tissues are therefore subjected to increased risk of thermal damage. In this study, for a number of clinically representative intercostal sonication geometries, modeling clinically available hardware, the effect of beam shaping on both the exposure of the ribs and near-field to acoustic energy was evaluated and the implications for the volumetric ablation rate were addressed. METHODS A relationship between rib temperature rise and acoustic energy density was established by means of in vivo MR thermometry and simulations of the incident acoustic energy for the corresponding anatomies. This relationship was used for interpretation of rib exposure in subsequent numerical simulations in which rib spacing, focal point placement, and the focal point trajectory were varied. The time required to heat a targeted region to 65 °C was determined without and with the application of beam shaping. The required sonication time was used to calculate the acoustic energy density at the fat-muscle interface and at the surface of the ribs. At the fat-muscle interface, exposure was compared to available literature data and rib exposure was interpreted based on the earlier obtained relation between measured temperature rise and simulated acoustic energy density. To estimate the volumetric ablation rate, the cool-down time between periods of energy exposure was estimated using a time-averaged power limit of 100 kJ/h. RESULTS At the level of the ribs, the temperature rise-energy density proportionality constant was estimated to be 6.0-7.6 °C/(J/mm(2)). Beam shaping by the geometric shadow method typically reduces the acoustic intensity a factor of 2, considering the 1 cm(2) with the highest exposure. For a 4 mm diameter circular sonication trajectory, the near-field energy limit of 2.5 J/mm(2) was exceeded for all considered geometries. The estimated rib temperature was in all but one (sonication 50 mm behind the ribs, with 15 mm rib spacing and a 4 mm diameter circular sonication trajectory) of the considered scenarios within acceptable limits. For those sonication scenarios where a single sonication is considered safe both in terms of near-field as well as rib heating, volumetric ablation rates in the order of 1 ml/h are estimated. CONCLUSIONS Intercostal sonication is associated with an increased risk of near-field overheating. This risk is strongly dependent on the considered rib spacing, the placement of the focus behind the ribs, and the selected sonication trajectory. For the hardware under simulation, obstruction by the thoracic cage renders ablations of clinically relevant volumes within a practical time-frame unfeasible in a large part of the liver. Improvements maybe expected from transducer designs with a larger active surface and/or nonlinear sonication strategies.

Antiglycolytic Therapy Combined with an Image-guided Minimally Invasive Delivery Strategy for the Treatment of Breast Cancer

PURPOSE The antiglycolytic agent 3-bromopyruvate (3-BrPA) promotes anticancer effects in multiple tumor models. This study evaluated the therapeutic efficacy of ultrasound (US)-guided intratumoral delivery of 3-BrPA in an orthotopic tumor model of breast cancer. MATERIALS AND METHODS Human breast cancer cell line MDA MB 231 was used for in vitro and in vivo studies. The anticancer effect of 3-BrPA was evaluated by viability assay, quantification of adenosine triphosphate (ATP) and lactate levels, and activity of matrix metalloproteinase (MMP)-9. In animal experiments, 15 nude mice with MDA MB 231 breast tumors were divided into three groups for US-guided intratumoral treatment with 1.75 mM 3-BrPA (group 1), 5 mM 3-BrPA (group 2), and saline solution (group 3). Tumor size was measured and subjected to histopathologic examination. RESULTS In vitro, treatment with 3-BrPA resulted in a dose-dependent decrease in cell viability. A decrease in ATP and lactate levels, invasion, and MMP9 activity and expression was observed after treatment with concentrations of 3-BrPA that did not affect cell viability. In vivo, a significant difference in tumor volume was observed between 3-BrPA-treated and control animals. At the end of the study, tumor volumes in the 3-BrPA groups were 1,876 mm(3)±346 and 426 mm(3)±180 in the 1.75-mM and 5-mM 3-BrPA groups, respectively, versus 4,447 mm(3)±571 in the control group (P< .05). CONCLUSIONS US-guided intratumoral injection of 3-BrPA effectively blocks breast cancer progression in an orthotopic mouse tumor model.

Procedural sedation and analgesia for respiratory-gated MR-HIFU in the liver: a feasibility study

BackgroundPrevious studies demonstrated both pre-clinically and clinically the feasibility of magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablations in the liver. To overcome the associated problem of respiratory motion of the ablation area, general anesthesia (GA) and mechanical ventilation was used in conjunction with either respiratory-gated energy delivery or energy delivery during induced apnea. However, clinical procedures requiring GA are generally associated with increased mortality, morbidity, and complication rate compared to procedural sedation and analgesia (PSA). Furthermore, PSA is associated with faster recovery and an increased eligibility for non- and mini-invasive interventions.MethodsIn this study, we investigate both in an animal model and on a small patient group the kinetics of the diaphragm during free-breathing, when a tailored remifentanil/propofol-based PSA protocol inducing partial respiratory depression is used. Subsequently, we demonstrate in an animal study the compatibility of the resulting respiratory pattern of the PSA protocol with a gated HIFU ablation in the liver by direct comparison with gated ablations conducted under GA. Wilcoxon signed-rank tests were performed for statistical analysis of non-perfused and necrosed tissue volumes. Duty cycles (ratio or percentage of the breathing cycle with the diaphragm in its resting position, such that acoustic energy delivery with MR-HIFU was allowed) were statistically compared for both GA and PSA using student’s t tests.ResultsIn both animal and human experiments, the breathing frequency was decreased below 9/min, while maintaining stable vital functions. Furthermore an end-exhalation resting phase was induced by this PSA protocol during which the diaphragm is virtually immobile. Median non-perfused volumes, non-viable volumes based on NADH staining, and duty cycles were larger under PSA than under GA or equal.ConclusionsWe conclude that MR-HIFU ablations of the liver under PSA are feasible and potentially increase the non-invasive nature of this type of intervention.

Spontaneous breathing vs . mechanical ventilation for respiratory-gated MR-HIFU ablation in the liver

Magnetic resonance-guided High Intensity Focused Ultrasound (MR-HIFU) ablation in the liver is complicated by the continuous motion of the target due to the respiratory cycle. Several motion compensation strategies have been proposed in the past, such as breath-holding, respiratory gating and dynamic beam steering. Respiratory gating for sonication and MR thermometry uses a pencil beam navigator on the diaphragm to limit power output and image acquisition to the resting phase of the diaphragm. Previously, we have used General Anesthesia with mechanical ventilation (GA) to obtain a long and reproducible resting phase of the diaphragm. From a patient’s perspective however, Procedural Sedation and Analgesia (PSA) has several advantages over GA such as a lower risk of complications and shorter recovery. In addition, it has lower associated costs and can be performed by non-anesthesiologists. The purpose of this animal study was to investigate the feasibility of respiratory-gated MR-HIFU ablation in the liver under PSA with spontaneous breathing.

Thermal ablation of a confluent lesion in the porcine kidney with a clinically available MR-HIFU system

The incidence of small renal masses (SRMs) sized  <4 cm has increased over the decades (as co-findings/or due to introduction of cross sectional imaging). Currently, partial nephrectomy (PN) or watchful waiting is advised in these patients. Ultimately, 80-90% of these SRMs require surgical treatment and PN is associated with a 15% complication rate. In this aging population, with possible comorbidities and poor health condition, both PN and watchful waiting are non-ideal treatment options. This resulted in an increased need for early, non-invasive treatment strategies such as MR-guided high intensity focused ultrasound (MR-HIFU). (i) To investigate the feasibility of creating a confluent lesion in the kidney using respiratory-gated MR-HIFU under clinical conditions in a pre-clinical study and (ii) to evaluate the reproducibility of the MR-HIFU ablation strategy. Healthy pigs (n  =  10) under general anesthesia were positioned on a clinical MR-HIFU system with integrated cooling. A honeycomb pattern of seven overlapping ablation cells (4  ×  4  ×  10 mm3, 450 W, <30 s) was ablated successively in the cortex of the porcine kidney. Both MR thermometry and acoustic energy delivery were respiratory gated using a pencil beam navigator on the contralateral kidney. The non-perfused volume (NPV) was visualized after the last sonication by contrast-enhanced (CE) T 1-weighted MR (T 1 w) imaging. Cell viability staining was performed to visualize the extent of necrosis. RESULTS a median NPV of 0.62 ml was observed on CE-T 1 w images (IQR 0.58-1.57 ml, range 0.33-2.75 ml). Cell viability staining showed a median damaged volume of 0.59 ml (IQR 0.24-1.35 ml, range 0-4.1 ml). Overlooking of the false rib, shivering of the pig, and too large depth combined with a large heat-sink effect resulted in insufficient heating in 4 cases. The NPV and necrosed volume were confluent in all cases in which an ablated volume could be observed. Our results demonstrated the feasibility of creating a confluent volume of ablated kidney cortical tissue in vivo with MR-HIFU on a clinically available system using respiratory gating and near-field cooling and showed its reproducibility.

Thermal ablation of a confluent lesion in the porcine kidney with magnetic resonance guided high intensity focused ultrasound

Since approximately 1.6 percent of men and women will be diagnosed with kidney and renal pelvis cancer during their lifetime, there is a growing interest in non-invasive kidney sparing therapy for renal cancer. As a consequence, several patient studies investigated the feasibility of high intensity focused ultrasound (HIFU) for the thermal ablation of renal masses. The majority of these studies used either a hand-held extracorporeal ultrasound transducer with ultrasound imaging for guidance or a laparoscopic approach. Drawbacks of these techniques are the lack of respiratory motion compensation, no means to observe the energy deposition in real time, the complexity of the probe positioning, and the risks of bleeding and tumor spillage. Alternatively, recent preclinical studies have demonstrated the feasibility of magnetic resonance guided high intensity focused ultrasound (MR-HIFU) interventions on the kidney with respect to motion compensated real-time thermometry and acoustic energy delivery. Here, we extend this prior work to investigate in an animal study if MR-HIFU can deliver a reliable confluent volumetric lesion in the renal cortex in a clinically relevant time-frame.