Abscopal Effects in Radio-Immunotherapy—Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

Immune checkpoint inhibition (ICI) targeting the programmed death receptor 1 (PD-1) has shown promising results in the fight against cancer. Systemic anti-tumor reactions due to radiation therapy (RT) can lead to regression of non-irradiated lesions (NiLs), termed “abscopal effect” (AbE). Combination of both treatments can enhance this effect. The aim of this study was to evaluate AbEs during anti-PD-1 therapy and irradiation. We screened 168 patients receiving pembrolizumab or nivolumab at our center. Inclusion criteria were start of RT within 1 month after the first or last application of pembrolizumab (2 mg/kg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks) and at least one metastasis outside the irradiation field. We estimated the total dose during ICI for each patient using the linear quadratic (LQ) model expressed as 2 Gy equivalent dose (EQD2) using α/β of 10 Gy. Radiological images were required showing progression or no change in NiLs before and regression after completion of RT(s). Images must have been acquired at least 4 weeks after the onset of ICI or RT. The surface areas of the longest diameters of the short- and long-axes of NiLs were measured. One hundred twenty-six out of 168 (75%) patients received ICI and RT. Fifty-three percent (67/126) were treated simultaneously, and 24 of these (36%) were eligible for lesion analysis. AbE was observed in 29% (7/24). One to six lesions (mean = 3 ± 2) in each AbE patient were analyzed. Patients were diagnosed with malignant melanoma (MM) (n = 3), non-small cell lung cancer (NSCLC) (n = 3), and renal cell carcinoma (RCC) (n = 1). They were irradiated once (n = 1), twice (n = 2), or three times (n = 4) with an average total EQD2 of 120.0 ± 37.7 Gy. Eighty-two percent of RTs of AbE patients were applied with high single doses. MM patients received pembrolizumab, NSCLC, and RCC patients received nivolumab for an average duration of 45 ± 35 weeks. We demonstrate that 29% of the analyzed patients showed AbE. Strict inclusion criteria were applied to distinguish the effects of AbE from the systemic effect of ICI. Our data suggest the clinical existence of systemic effects of irradiation under ICI and could contribute to the development of a broader range of cancer treatments

High Intensity Focused Ultrasound for Treatment of Bone Malignancies—20 Years of History

High Intensity Focused Ultrasound (HIFU) is the only non-invasive method for percutaneous thermal ablation of tissue, with treatments typically performed either under magnetic resonance imaging or ultrasound guidance. Since this method allows efficient heating of bony structures, it has found not only early use in treatment of bone pain, but also in local treatment of malignant bone tumors. This review of 20 years of published studies shows that HIFU is a very efficient method for rapid pain relief, can provide local tumor control and has a very patient-friendly safety profile

A time-driven activity-based costing approach of magnetic resonance-guided high-intensity focused ultrasound for cancer-induced bone pain

Objective To determine resource consumption and total costs for providing magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) treatment to a patient with cancer-induced bone pain (CIBP). Methods We conducted a time-driven activity-based costing (TD-ABC) of MR-HIFU treatments for CIBP from a hospital perspective. A European care-pathway (including a macro-, meso-, and micro-level) was designed to incorporate the care-delivery value chain. Time estimates were obtained from medical records and from prospective direct observations. To calculate the capacity cost rate, data from the controlling department of a German university hospital were allocated to the modules of the care pathway. Best- and worst-case scenarios were calculated by applying lower and upper bounds of time measurements. Results The macro-level care pathway consisted of eight modules (i.e., outpatient consultations, pretreatment imaging, preparation, optimization, sonication, post-treatment, recovery, and anesthesia). The total cost of an MR-HIFU treatment amounted to euro5147 per patient. Best- and worst-case scenarios yielded a total cost of euro4092 and to euro5876. According to cost categories, costs due to equipment accounted for 41% of total costs, followed by costs with personnel (32%), overhead (16%) and materials (11%). Conclusion MR-HIFU is an emerging noninvasive treatment for alleviating CIBP, with increasing evidence on treatment efficacy. This costing study can support MR-HIFU reimbursement negotiations and facilitate the adoption of MR-HIFU as first-line treatment for CIBP. The present TD-ABC model creates the opportunity of benchmarking the provision of MR-HIFU to bone tumor

Temperature-sensitive paramagnetic liposomes for image-guided drug delivery: Mn2+ versus [Gd(HPDO3A)(H2O)]

Temperature-sensitive liposomes (TSLs) loaded with doxorubicin (Dox), and Magnetic Resonance Imaging contrast agents (CAs), either manganese (Mn2 +) or [Gd(HPDO3A)(H2O)], provide the advantage of drug delivery under MR image guidance. Encapsulated MRI CAs have low longitudinal relaxivity (r1) due to limited transmembrane water exchange. Upon triggered release at hyperthermic temperature, the r1 will increase and hence, provides a means to monitor drug distribution in situ. Here, the effects of encapsulated CAs on the phospholipid bilayer and the resulting change in r1 were investigated using MR titration studies and 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles. Our results show that Mn2 + interacted with the phospholipid bilayer of TSLs and consequently, reduced doxorubicin retention capability at 37 °C within the interior of the liposomes over time. Despite that, Mn2 +-phospholipid interaction resulted in higher r1 increase, from 5.1 ± 1.3 mM− 1 s− 1 before heating to 32.2 ± 3 mM− 1 s− 1 after heating at 60 MHz and 37 °C as compared to TSL(Gd,Dox) where the longitudinal relaxivities before and after heating were 1.2 ± 0.3 mM− 1 s− 1 and 4.4 ± 0.3 mM− 1 s− 1, respectively. Upon heating, Dox was released from TSL(Mn,Dox) and complexation of Mn2 + to Dox resulted in a similar Mn2 + release profile. From 25 to 38 °C, r1 of [Gd(HPDO3A)(H2O)] gradually increased due to increase transmembrane water exchange, while no Dox release was observed. From 38 °C, the release of [Gd(HPDO3A)(H2O)] and Dox was irreversible and the release profiles coincided. By understanding the non-covalent interactions between the MRI CAs and phospholipid bilayer, the properties of the paramagnetic TSLs can be tailored for MR guided drug delivery

Bone metastasis treatment using magnetic resonance-guided high intensity focused ultrasound

Objectives: Bone pain resulting from cancer metastases reduces a patient's quality of life. Magnetic Resonance-guided High Intensity Focused Ultrasound (MR-HIFU) is a promising alternative palliative thermal treatment technique for bone metastases that has been tested in a few clinical studies. Here, we describe a comprehensive pre-clinical study to investigate the effects, and efficacy of MR-HIFU ablation for the palliative treatment of osteoblastic bone metastases in rats. Materials and methods: Prostate cancer cells (MATLyLu) were injected intra-osseously in Copenhagen rats. Upon detection of pain, as determined with a dynamic weight bearing (DWB) system, a MR-HIFU system was used to thermally ablate the bone region with tumor. Treatment effect and efficacy were assessed using magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) with technetium-99m medronate (99mTc-MDP), micro-computed tomography (μCT) and histology. Results: DWB analysis demonstrated that MR-HIFU-treated animals retained 58.6±20.4% of limb usage as compared to 2.6±6.3% in untreated animals (P=0.003). MR-HIFU delayed tumor specific growth rates (SGR) from 29±6 to 13±5%/day (P3) had a greater accumulation of 99mTc-MDP than HIFU-treated animals (127.0±42.7mm3, P=0.004). The total bone volume increase for untreated and HIFU-treated animals was 15.6±9.6% and 3.0±4.1% (P=0.004), respectively. Histological analysis showed ablation of nerve fibers, tumor, inflammatory and bone cells. Conclusions: Our study provides a detailed characterization of the effects of MR-HIFU treatment on bone metastases, and provides fundamental data, which may motivate and advance its use in the clinical treatment of painful bone metastases with MR-HIFU

Effects of magnetic resonance-guided high-intensity focused ultrasound ablation on bone mechanical properties and modeling

BACKGROUND: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a promising technique for palliative treatment of bone pain. In this study, the effects of MR-HIFU ablation on bone mechanics and modeling were investigated. METHODS: A total of 12 healthy rat femurs were ablated using 10 W for 46 ± 4 s per sonication with 4 sonications for each femur. At 7 days after treatments, all animals underwent MR and single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Then, six animals were euthanized. At 1 month following ablations, the remaining six animals were scanned again with MR and SPECT/CT prior to euthanization. Thereafter, both the HIFU-treated and contralateral control bones of three animals from each time interval were processed for histology, whereas the remaining bones were subjected to micro-CT (μCT), three-point bending tests, and micro-finite element (micro-FE) analyses. RESULTS: At 7 days after HIFU ablations, edema formation around the treated bones coupled with bone marrow and cortical bone necrosis was observed on MRI and histological images. SPECT/CT and μCT images revealed presence of bone modeling through an increased uptake of (99m)Tc-MDP and formation of woven bone, respectively. At 31 days after ablations, as illustrated by imaging and histology, healing of the treated bone and the surrounding soft tissue was noted, marked by decreased in amount of tissue damage, formation of scar tissue, and sub-periosteal reaction. The results of three-point bending tests showed no significant differences in elastic stiffness, ultimate load, and yield load between the HIFU-treated and contralateral control bones at 7 days and 1 month after treatments. Similarly, the elastic stiffness and Young's moduli determined by micro-FE analyses at both time intervals were not statistically different. CONCLUSIONS: Multimodality imaging and histological data illustrated the presence of HIFU-induced bone damage at the cellular level, which activated the bone repair mechanisms. Despite that, these changes did not have a mechanical impact on the bone

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Technical Background and Overview of Current Clinical Applications (Part 1)

Background Extracorporeal high-intensity focused ultrasound (HIFU) is a promising method for the noninvasive thermal ablation of benign and malignant tissue. Current HIFU treatments are performed under ultrasound (US-HIFU) or magnetic resonance (MR-HIFU) image guidance offering integrated therapy planning, real-time control (spatial and temperature guidance) and evaluation. Methods This review is based on publications in peer-reviewed journals addressing thermal ablation using HIFU and includes our own clinical results as well. The technical background of HIFU is explained with an emphasis on MR-HIFU applications. A brief overview of the most commonly performed CE-approved clinical applications for MR-HIFU is given. Results Over the last decade, several HIFU-based applications have received clinical approval in various countries. In particular, MR-HIFU is now approved for the clinical treatment of uterine fibroids, palliation of bone pain, ablation of the prostate and treatment of essential tremor as a first neurological application. Conclusion MR-HIFU is a patient-friendly noninvasive method for thermal ablation which has received clinical approval for several applications. Overall, clinical data demonstrate treatment efficacy, safety and cost efficiency. Key Points: HIFU is a promising technique for noninvasive thermal ablation of tissue. HIFU is typically performed under image guidance using either diagnostic ultrasound (US-HIFU) or MRI (MR-HIFU). The preferred image guidance modality depends on the application. MR guidance offers improved soft-tissue contrast for treatment planning, near real-time and noninvasive temperature monitoring and post-interventional therapy evaluation. MR-HIFU is CE-approved for treatment of uterine fibroids, alleviation of bone pain, prostate tissue ablation and treatment of essential tremor

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Overview of Emerging Applications (Part 2)

Background High-intensity focused ultrasound (HIFU) allows noninvasive heating of deep-seated tissues. Guidance under magnetic resonance imaging (MR-HIFU) offers spatial targeting based on anatomical MR images as well as MR-based near-real-time temperature maps. Temperature feedback allows delivery of a well-defined thermal dose enabling new applications such as the ablation of malignant tissue. Methods Peer-reviewed publications on MR-HIFU were studied and are summarized in this review. Literature was restricted to applications in oncology. Results Several MR-HIFU-based applications for the treatment of malignant diseases are currently part of clinical trials or translational research. Recent trials regarding the treatment of prostate cancer with MR-HIFU have already shown this to be a safe and patient-friendly method. For the treatment of breast cancer and malignancies within abdominal organs, MR-HIFU has been applied so far only in proof of concept studies. Conclusion MR-HIFU is currently being investigated for the ablative treatment of malignant tissue in a variety of oncological applications. For example, the transrectal as well as transurethral ablation of prostate cancer using MR-HIFU was shown to be a patient-friendly, safe alternative to other local treatment options with low side effects. Key points: MR guidance offers high soft tissue contrast for treatment planning, near-real-time temperature monitoring, and post-interventional therapy evaluation. Special HIFU transducers and technological solutions are available for the treatment of e.g. prostate cancer, breast cancer or abdominal malignancies

Feasibility study of MR-guided pancreas ablation using high-intensity focused ultrasound in a healthy swine model

Purpose:Pancreatic cancer is typically diagnosed in a late stage with limited therapeutic options. For those patients, ultrasound-guided high-intensity focused ultrasound (US-HIFU) can improve local control and alleviate pain. However, MRI-guided HIFU (MR-HIFU) has not yet been studied extensively in this context. To facilitate related research and accelerate clinical translation, we report a workflow for thein vivoHIFU ablation of the porcine pancreas under MRI guidance. Materials and methods:The pancreases of five healthy German landrace pigs (35-58 kg) were sonicated using a clinical MR-HIFU system. Acoustic access to the pancreas was supported by a specialized diet and a hydrogel compression device for bowel displacement. Organ motion was suspended using periods of apnea. The size of the resulting thermal lesions was assessed using the thermal threshold- and dose profiles, non-perfused volume, and gross examination. The effect of the compression device on beam path length was assessed using MRI imaging. Results:Eight of ten treatments resulted in clearly visible damage in the target tissue upon gross examination. Five treatments resulted in coagulative necrosis. Good agreement between the four metrics for lesion size and a clear correlation between the delivered energy dose and the resulting lesion size were found. The compression device notably shortened the intra-abdominal beam path. Conclusions:We demonstrated a workflow for HIFU treatment of the porcine pancreas in-vivo under MRI-guidance. This development bears significance for the development of MR-guided HIFU interventions on the pancreas as the pig is the preferred animal model for the translation of pre-clinical research into clinical application