Integrated thermal and magnetic susceptibility modeling for air-motion artifact correction in proton resonance frequency shift thermometry.

PURPOSE: Hyperthermia treatments are successful adjuvants to conventional cancer therapies in which the tumor is sensitized by heating. To monitor and guide the hyperthermia treatment, measuring the tumor and healthy tissue temperature is important. The typical clinical practice heavily relies on intraluminal probe measurements that are uncomfortable for the patient and only provide spatially sparse temperature information. A solution may be offered through recent advances in magnetic resonance thermometry, which allows for three-dimensional internal temperature measurements. However, these measurements are not widely used in the pelvic region due to a low signal-to-noise ratio and presence of image artifacts. METHODS: To advance the clinical integration of magnetic resonance-guided cancer treatments, we consider the problem of removing air-motion-induced image artifacts. Thereto, we propose a new combined thermal and magnetic susceptibility model-based temperature estimation scheme that uses temperature estimates to improve the removal of air-motion-induced image artifacts. The method is experimentally validated using a dedicated phantom that enables the controlled injection of air-motion artifacts and with in vivo thermometry from a clinical hyperthermia treatment. RESULTS: We showed, using probe measurements in a heated phantom, that our method reduced the mean absolute error (MAE) by 58% compared to the state-of-the-art near a moving air volume. Moreover, with in vivo thermometry our method obtained a MAE reduction between 17% and 95% compared to the state-of-the-art. CONCLUSION: We expect that the combined thermal and magnetic susceptibility modeling used in model-based temperature estimation can significantly improve the monitoring in hyperthermia treatments and enable feedback strategies to further improve MR-guided hyperthermia cancer treatments.

Recent technological advancements in radiofrequency- andmicrowave-mediated hyperthermia for enhancing drug delivery.

Hyperthermia therapy is a potent enhancer of chemotherapy and radiotherapy. In particular, microwave (MW) and radiofrequency (RF) hyperthermia devices provide a variety of heating approaches that can treat most cancers regardless the size. This review introduces the physics of MW/RF hyperthermia, the current state-of-the-art systems for both localized and regional heating, and recent advancements in hyperthermia treatment guidance using real-time computational simulations and magnetic resonance thermometry. Clinical trials involving RF/MW hyperthermia as adjuvant for chemotherapy are also presented per anatomical site. These studies favor the use of adjuvant hyperthermia since it significantly improves curative and palliative clinical outcomes. The main challenge of hyperthermia is the distribution of state-of-the-art heating systems. Nevertheless, we anticipate that recent technology advances will expand the use of hyperthermia to chemotherapy centers for enhanced drug delivery. These new technologies hold great promise not only for (image-guided) perfusion modulation and sensitization for cytotoxic drugs, but also for local delivery of various compounds using thermosensitive liposomes.

The potential of constrained SAR focusing for hyperthermia treatment planning: analysis for the head & neck region.

Clinical trials have shown that hyperthermia is a potent adjuvant to conventional cancer treatments, but the temperatures currently achieved in the clinic are still suboptimal. Hyperthermia treatment planning simulations have potential to improve the heating profile of phased-array applicators. An important open challenge is the development of an effective optimization procedure that enables uniform heating of the target region while keeping temperature below a threshold in healthy tissues. In this work, we analyzed the effectiveness and efficiency of a recently proposed optimization approach, i.e. focusing via constrained power optimization (FOCO), using 3D simulations of twelve clinical patient specific models. FOCO performance was compared against a clinically used particle swarm based optimization approach. Evaluation metrics were target coverage at the 25% iso-SAR level, target hotspot quotient, median target temperature (T50) and computational requirements. Our results show that, on average, constrained power focusing performs slightly better than the clinical benchmark ([Formula: see text]T50 [Formula: see text] °C), but outperforms this clinical benchmark for large target volumes ([Formula: see text]40 cm[Formula: see text], [Formula: see text]T50 [Formula: see text] °C). In addition, the results are achieved in a shorter time ([Formula: see text]%) and are repeatable because the approach is formulated as a convex optimization problem.

The potential of time-multiplexed steering in phased array microwave hyperthermia for head and neck cancer treatment.

Clinical studies have shown that hyperthermia sensitizes tumor cells for conventional therapies. During phased-array microwave hyperthermia, an array of antennas is used to focus the electromagnetic waves at the target region. Selective heating, while preserving the healthy tissue, is a demanding challenge and currently patient specific pre-treatment planning is used to optimize the amplitudes and phases of the waves. In addition, when needed, this single optimal heat distribution is adapted using the simulations based on the feedback from thermo-sensors and the patient. In this paper, we hypothesize that sequential, i.e. 'time-multiplexed', application of multiple Pareto optimal heating patterns provides a better time-averaged treatment quality. To test the benefit of such a time-multiplexed approach, a multi-objective genetic algorithm was introduced to balance two objectives that both focus the specific absorption rate (SAR) delivered to the target region but differ in the suppressing of pre-defined hotspots. This step leads to two Pareto optimal distributions. These 'diverse' antenna settings are then applied sequentially and thermal simulations are used to evaluate the effectiveness of the time-multiplexed steering. The proposed technique is tested using treatment planning data of a representative dataset of five head and neck patients for the HYPERcollar3D. Steering dynamics are analysed and the time-multiplexed steering is compared to the current static solution used in the clinic, i.e. hotspot-target SAR quotient optimization using particle swarm optimization. Our results demonstrate that realistic steering periods of 10s suffice to stabilize temperatures within 0.04 °C and the ability to enhance target heating while reducing hotspots, i.e. 0.3 °C-1.2 °C improvement in T 50 while reducing hotspot temperatures by 0.6 °C-1.5 °C.

Deep hyperthermia with the HYPERcollar system combined with irradiation for advanced head and neck carcinoma - a feasibility study.

PURPOSE: Radiotherapy (RT) treatment of locally-advanced and recurrent head and neck carcinoma (HNC) results in disappointing outcomes. Combination of RT with cisplatin or cetuximab improves survival but the increased toxicity and patient's comorbidity warrant the need for a less-toxic radiosensitizer. Stimulated by several randomized studies demonstrating the radio-sensitizing effect of hyperthermia, we developed the HYPERcollar. Here, we report early experience and toxicity in patients with advanced HNC. METHODS AND MATERIALS: 119 hyperthermia treatments given to 27 patients were analyzed. Hyperthermia was applied once a week by the HYPERcollar aimed at achieving 39-43 °C in the target area, up to patients' tolerance. Pre-treatment planning was used to optimize treatment settings. When possible, invasive thermometry catheters were placed. RESULTS: Mean power applied during the 119 hyperthermia treatments ranged from 120 to 1007 W (median 543 W). 15 (13%) hyperthermia treatments were not fully completed due to: pain allocated to hyperthermia (6/15), dyspnea from sticky saliva associated with irradiation (2/15) and unknown reasons (7/15). No severe complications or enhanced thermal or mucosal toxicities were observed. Excluding post-operative treatment, response rates after 3 months were 46% (complete) and 7% (partial). CONCLUSION: Hyperthermia with the HYPERcollar proved to be safe and feasible with good compliance and promising outcome.

A printed Yagi-Uda antenna for application in magnetic resonance thermometry guided microwave hyperthermia applicators.

Biological studies and clinical trials show that addition of hyperthermia stimulates conventional cancer treatment modalities and significantly improves treatment outcome. This supra-additive stimulation can be optimized by adaptive hyperthermia to counteract strong and dynamic thermoregulation. The only clinically proven method for the 3D non-invasive temperature monitoring required is by magnetic resonance (MR) temperature imaging, but the currently available set of MR compatible hyperthermia applicators lack the degree of heat control required. In this work, we present the design and validation of a high-frequency (433 MHz ISM band) printed circuit board antenna with a very low MR-footprint. This design is ideally suited for use in a range of hyperthermia applicator configurations. Experiments emulating the clinical situation show excellent matching properties of the antenna over a 7.2% bandwidth (S 11 < -15 dB). Its strongly directional radiation properties minimize inter-element coupling for typical array configurations (S 21 < -23 dB). MR imaging distortion by the antenna was found negligible and MR temperature imaging in a homogeneous muscle phantom was highly correlated with gold-standard probe measurements (root mean square error: RMSE = 0.51 °C and R 2 = 0.99). This work paves the way for tailored MR imaging guided hyperthermia devices ranging from single antenna or incoherent antenna-arrays, to real-time adaptive hyperthermia with phased-arrays.

Differential Evolution Optimization of the SAR Distribution for Head and Neck Hyperthermia.

Hyperthermia is an emerging cancer treatment modality, which involves applying heat to the malignant tumor. The heating can be delivered using electromagnetic (EM) energy, mostly in the radiofrequency (RF) or microwave range. Accurate patient-specific hyperthermia treatment planning (HTP) is essential for effective and safe treatments, in particular, for deep and loco-regional hyperthermia. An important aspect of HTP is the ability to focus microwave energy into the tumor and reduce the occurrence of hot spots in healthy tissue. This paper presents a method for optimizing the specific absorption rate (SAR) distribution for the head and neck cancer hyperthermia treatment. The SAR quantifies the rate at which localized RF or microwave energy is absorbed by the biological tissue when exposed to an EM field. A differential evolution (DE) optimization algorithm is proposed in order to improve the SAR coverage of the target region. The efficacy of the proposed algorithm is demonstrated by testing with the Erasmus MC patient dataset. DE is compared to the particle swarm optimization (PSO) method, in terms of average performance and standard deviation and across various clinical metrics, such as the hot-spot-tumor SAR quotient (HTQ), treatment quantifiers, and temperature parameters. While hot spots in the SAR distribution remain a problem with current approaches, DE enhances focusing microwave energy absorption to the target region during hyperthermia treatment. In particular, DE offers improved performance compared to the PSO algorithm currently deployed in the clinic, reporting a range of improvement of HTQ standard deviation of between 40.1-96.8% across six patients.

Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future.

Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities.

Laboratory prototype for experimental validation of MR-guided radiofrequency head and neck hyperthermia.

Clinical studies have established a strong benefit from adjuvant mild hyperthermia (HT) to radio- and chemotherapy for many tumor sites, including the head and neck (H&N). The recently developed HYPERcollar allows the application of local radiofrequency HT to tumors in the entire H&N. Treatment quality is optimized using electromagnetic and thermal simulators and, whenever placement risk is tolerable, assessed using invasively placed thermometers. To replace the current invasive procedure, we are investigating whether magnetic resonance (MR) thermometry can be exploited for continuous and 3D thermal dose assessment. In this work, we used our simulation tools to design an MR compatible laboratory prototype applicator. By simulations and measurements, we showed that the redesigned patch antennas are well matched to 50 Ω (S11<-10 dB). Simulations also show that, using 300 W input power, a maximum specific absorption rate (SAR) of 100 W kg(-1) and a temperature increase of 4.5 °C in 6 min is feasible at the center of a cylindrical fat/muscle phantom. Temperature measurements using the MR scanner confirmed the focused heating capabilities and MR compatibility of the setup. We conclude that the laboratory applicator provides the possibility for experimental assessment of the feasibility of hybrid MR-HT in the H&N region. This versatile design allows rigorous analysis of MR thermometry accuracy in increasingly complex phantoms that mimic patients' anatomies and thermodynamic characteristics.

Electromagnetic redesign of the HYPERcollar applicator: toward improved deep local head-and-neck hyperthermia.

Accumulating evidence shows that hyperthermia improves head-and-neck cancer treatment. Over the last decade, we introduced a radiofrequency applicator, named HYPERcollar, which enables local heating also of deep locations in this region. Based on clinical experience, we redesigned the HYPERcollar for improved comfort, reproducibility and operator handling. In the current study, we analyze the redesign from an electromagnetic point of view. We show that a higher number of antennas and their repositioning allow for a substantially improved treatment quality. Combined with the much better reproducibility of the water bolus, this will substantially minimize the risk of underexposure. All improvements combined enable a reduction of hot-spot prominence (hot-spot to target SAR quotient) by 32% at an average of 981 W, which drastically reduces the probability for system power to become a treatment limiting source. Moreover, the power deposited in the target selectively can be increased by more than twofold. Hence, we expect that the HYPERcollar redesign currently under construction allows us to double the clinically applied power to the target while reducing the hot-spots, resulting in higher temperatures and, consequently, better clinical outcome.

Benefit of replacing the Sigma-60 by the Sigma-Eye applicator. A Monte Carlo-based uncertainty analysis.

BACKGROUND AND PURPOSE: To investigate the clinical benefit of replacing the BSD-2000 Sigma-60 with the Sigma-Eye applicator, taking into account effects of uncertainties in tissue and water bolus parameters. PATIENTS AND METHODS: For 20 patients, specific absorption rate (SAR) and temperature distributions were calculated and optimized, based on computed tomography (CT) scans in treatment position. The impact of uncertainties on predicted distributions was studied using a Monte Carlo uncertainty assessment. RESULTS: Replacing the Sigma-60 by the Sigma-Eye applicator resulted in a higher SAR in the tumor [on average a decrease of the hotspot tumor quotient (HTQ) by 24%; p < 0.001], and higher temperatures (T90: +0.4°C, p < 0.001; T50: +0.6°C, p < 0.001) using literature values and SAR optimization. When temperature optimization (T90) was used, a larger average increase was found (T90: +0.7°C, p < 0.001; T50: +0.8°C, p < 0.001). When taking into account uncertainties, a decrease of 23% in median HTQ (p < 0.001) and an increase in T50 and T90 of 0.4°C (p < 0.001) could be demonstrated. CONCLUSION: Based on this uncertainty analysis, significant and clinically relevant improvements in HTQ and tumor temperature were achieved when replacing the Sigma-60 by the Sigma-Eye applicator.

Reconstruction of applicator positions from multiple-view images for accurate superficial hyperthermia treatment planning.

In the current clinical practice, prior to superficial hyperthermia treatments (HT), temperature probes are placed in tissue to document a thermal dose. To investigate whether the painful procedure of catheter placement can be replaced by superficial HT planning, we study if the specific absorption rate (SAR) coverage is predictive for treatment outcome. An absolute requirement for such a study is the accurate reconstruction of the applicator setup. The purpose of this study was to investigate the feasibility of the applicator setup reconstruction from multiple-view images. The accuracy of the multiple-view reconstruction method has been assessed for two experimental setups using six lucite cone applicators (LCAs) representing the largest array applied at our clinic and also the most difficult scenario for the reconstruction. For the two experimental setups and 112 distances, the mean difference between photogrametry reconstructed and manually measured distances was 0.25 ± 0.79 mm (mean±1 standard deviation). By a parameter study of translation T (mm) and rotation R (°) of LCAs, we showed that these inaccuracies are clinically acceptable, i.e. they are either from ±1.02 mm error in translation or ±0.48° in rotation, or combinations expressed by 4.35R(2) + 0.97T(2) = 1. We anticipate that such small errors will not have a relevant influence on the SAR distribution in the treated region. The clinical applicability of the procedure is shown on a patient with a breast cancer recurrence treated with reirradiation plus superficial hyperthermia using the six-LCA array. The total reconstruction procedure of six LCAs from a set of ten photos currently takes around 1.5 h. We conclude that the reconstruction of superficial HT setup from multiple-view images is feasible and only minor errors are found that will have a negligible influence on treatment planning quality.

The clinical feasibility of deep hyperthermia treatment in the head and neck: new challenges for positioning and temperature measurement.

To apply high-quality hyperthermia treatment to tumours at deep locations in the head and neck (H&N), we have designed and built a site-specific phased-array applicator. Earlier, we demonstrated its features in parameter studies, validated those by phantom measurements and clinically introduced the system. In this paper we will critically review our first clinical experiences and demonstrate the pivotal role of hyperthermia treatment planning (HTP). Three representative patient cases (thyroid, oropharynx and nasal cavity) are selected and discussed. Treatment planning, the treatment, interstitially measured temperatures and their interrelation are analysed from a physics point of view. Treatments lasting 1 h were feasible and well tolerated and no acute treatment-related toxicity has been observed. Maximum temperatures measured are in the range of those obtained during deep hyperthermia treatments in the pelvic region but mean temperatures are still to be improved. Further, we found that simulated power absorption correlated well with measured temperatures illustrating the validity of our treatment approach of using energy profile optimizations to arrive at higher temperatures. This is the first data proving that focussed heating of tumours in the H&N is feasible. Further, HTP proved a valuable tool in treatment optimization. Items to improve are (1) the transfer of HTP settings into the clinic and (2) the registration of the thermal dose, i.e. dosimetry.

Design and test of a 434 MHz multi-channel amplifier system for targeted hyperthermia applicators.

PURPOSE: For our head-and-neck hyperthermia (HT) applicator, an amplifier system with full amplitude and phase-control to deliver the radio-frequency signals, was not available. We therefore designed and tested a 433.92 MHz multi-channel amplifier system. SYSTEM DESCRIPTION: The design consists of a direct digital synthesizer (DDS) system that generates 12 phase-controlled coherent 433.92 MHz signals, which are amplified to maximum 200 W output per channel. Directional couplers are placed at the amplifiers to couple a small portion of both forward and reflected signals to gain-and-phase detectors. The power setting is applied with a resolution of 2 W and for the phase it is 0.1 degrees . The channels are sequentially sampled at 100 Hz per channel. METHODS: We tested the performance of the designed amplifier system by measuring the RF spectrum, power and phase accuracy, and by characterising the feedback control by using highly accurate power and phase meters. RESULTS: The spurious emission is less than 60 dBc and the first two harmonic frequencies are suppressed more than 45 dB. The measurement accuracy for the power (+/-5%) is valid for at least 20 days after calibration and for the phase (+/-5 degrees ) it is valid for at least 2 months. CONCLUSIONS: The amplifier system operates according to our design criteria to support targeted HT. It can be used for both our in-house developed superficial and head-and-neck HT applicators or any other HT applicator that works on the same frequency of 433.92 MHz.

Patient positioning in deep hyperthermia: influences of inaccuracies, signal correction possibilities and optimization potential.

In this deep hyperthermia study, the robustness of SAR (specific absorption rate) patterns to patient-position variations is assessed, as well as the possibilities to correct for improper positioning and the benefits of non-standard positions. With a finite element model, the SAR distributions were predicted for ten patients at 33 positions. Position sensitivity is assessed for both SAR-focus steering, i.e. settings based on a calculated focus in a cylindrical patient representation, and HTP (hyperthermia treatment planning)-guided steering, i.e. model-based optimization of the SAR distribution. Position inaccuracies of less than 1 cm do not significantly affect SAR patterns. For SAR-focus steering, the SAR maximum is not always at the desired focus location, especially in the Y (anterior/posterior)- and Z (axial)-directions. For a maximum shift of 5 cm in all directions, both SAR-focus steering and HTP-guided steering are suitable to correct for improper positioning up to the level that none of the investigated positions appears preferable. Current positioning precision is sufficient in the X (right-left)-direction, but precision measurements are needed to reach the desired accuracy in the Y-direction. In the Z-direction, a cranial shift of the applicator is predicted to be beneficial. If the position is known accurately, correction of the treatment setting is possible without loss of heating efficiency. Additionally, no preferable positions exist.

An ultrasound cylindrical phased array for deep heating in the breast: theoretical design using heterogeneous models.

The objective of this theoretical study is to design an ultrasound (US) cylindrical phased array that can be used for hyperthermia (40-44 degrees C) treatment of tumours in the intact breast. Simultaneously, we characterize the influence of acoustic and thermal heterogeneities on the specific absorption rate (SAR) and temperature patterns to determine the necessity of using heterogeneous models for a US applicator design and treatment planning. Cylindrical configurations of monopole transducers are studied on their ability to generate interference patterns that can be steered electronically to the location of the target region. Hereto, design parameters such as frequency, number of transducers per ring, ring distance and number of rings are optimized to obtain a small primary focus, while suppressing secondary foci. The models account for local heterogeneities in both acoustic (wave velocity and absorption) and thermal (blood perfusion rate, heat capacity and conductivity) tissue properties. We used breast models with a central tumour (30x20x38 mm3) and an artificial thorax tumour (sphere with a radius of 25 mm) to test the design. Simulations predict that a US cylindrical phased array, consisting of six rings with 32 transducers per ring, a radius of 75 mm and 66 mm distance between the first and sixth transducer ring, operating at a frequency of 100 kHz, can be used to obtain 44 degrees C in the centre of tumours located anywhere in the intact breast. The dimensions of the volumes enclosed by the 41 degrees C iso-temperature are 19x19x21 mm3 and 21x21x32 mm3 for the central and the thorax tumours, respectively. It is demonstrated that acoustic and thermal heterogeneities do not disturb the SAR and temperature patterns.

Winner of the "New Investigator Award" at the European Society of Hyperthermia Oncology Meeting 2007. The HYPERcollar: a novel applicator for hyperthermia in the head and neck.

The purpose of this work was to define all features, and show the potential, of the novel HYPERcollar applicator system for hyperthermia treatments in the head and neck region. The HYPERcollar applicator consists of (1) an antenna ring, (2) a waterbolus system and (3) a positioning system. The specific absorption rate (SAR) profile of this applicator was investigated by performing infra-red measurements in a cylindrical phantom. Mandatory patient-specific treatment planning was performed as an object lesson to a patient with a laryngeal tumour and an artificial lymph node metastasis. Comfort tests with healthy volunteers have revealed that the applicator provides sufficient comfort to maintain in treatment position for an hour: the standard hyperthermia treatment duration in our centre. By phantom measurements, we established that a central focus in the neck can be obtained, with 50% iso-SAR lengths of 3.5 cm in transversal directions (x/y) and 9-11 cm in the axial direction (z). Using treatment planning by detailed electromagnetic simulations, we showed that the SAR pattern can be optimised to enable simultaneous encompassing of a primary laryngeal tumour and a lymph node metastasis at the 25% iso-SAR level. This study shows that the applicator enables a good control, and sufficient possibilities for optimisation, of the SAR pattern. In an ongoing clinical feasibility study, we will investigate the possibilities of heating various target regions in the neck with this apparatus.

Assessment of the local SAR distortion by major anatomical structures in a cylindrical neck phantom.

The objective of this work is to gain insight in the distortions on the local SAR distribution by various major anatomical structures in the neck. High resolution 3D FDTD calculations based on a variable grid are made for a semi-3D generic phantom based on average dimensions obtained from CT-derived human data and in which simplified structures representing trachea, cartilage, spine and spinal cord are inserted. In addition, phantoms with dimensions equal to maximum and minimum values within the CT-derived data are also studied. In all cases, the phantoms are exposed to a circular coherent array of eight dipoles within a water bolus and driven at 433 MHz. Comparisons of the SAR distributions due to individual structures or a combination of structures are made relative to a cylindrical phantom with muscle properties. The calculations predict a centrally located region of high SAR within all neck phantoms. This focal region, expressed as contours at either 50% or 75% of the peak SAR, changes from a circular cross-section in the case of the muscle phantom to a doughnut shaped region when the anatomical structures are present. The presence of the spine causes the greatest change in the SAR distribution, followed closely by the trachea. Global changes in the mean SAR relative to the uniform phantom are <11%, whilst local changes are as high as 2.7-fold. There is little difference in the focal dimensions between the average and smallest phantoms, but a decrease in the focal region is seen in the case of the largest phantom. This study presents a first step towards understanding of the complex influences of the various parameters on the SAR pattern which will facilitate the design of a site-specific head and neck hyperthermia applicator.