Biological modeling in thermoradiotherapy: present status and ongoing developments toward routine clinical use.

Biological modeling for anti-cancer treatments using mathematical models can be very supportive in gaining more insight into dynamic processes responsible for cellular response to treatment, and predicting, evaluating and optimizing therapeutic effects of treatment. This review presents an overview of the current status of biological modeling for hyperthermia in combination with radiotherapy (thermoradiotherapy). Various distinct models have been proposed in the literature, with varying complexity; initially aiming to model the effect of hyperthermia alone, and later on to predict the effect of the combined thermoradiotherapy treatment. Most commonly used models are based on an extension of the linear-quadratic (LQ)-model enabling an easy translation to radiotherapy where the LQ model is widely used. Basic predictions of cell survival have further progressed toward 3 D equivalent dose predictions, i.e., the radiation dose that would be needed without hyperthermia to achieve the same biological effect as the combined thermoradiotherapy treatment. This approach, with the use of temperature-dependent model parameters, allows theoretical evaluation of the effectiveness of different treatment strategies in individual patients, as well as in patient cohorts. This review discusses the significant progress that has been made in biological modeling for hyperthermia combined with radiotherapy. In the future, when adequate temperature-dependent LQ-parameters will be available for a large number of tumor sites and normal tissues, biological modeling can be expected to be of great clinical importance to further optimize combined treatments, optimize clinical protocols and guide further clinical studies.

A moderate thermal dose is sufficient for effective free and TSL based thermochemotherapy.

Hyperthermia, i.e. heating the tumor to a temperature of 40-43 °C is considered by many a valuable treatment to sensitize tumor cells to radiotherapy and chemotherapy. In recent randomized trials the great potential of adding hyperthermia to chemotherapy was demonstrated for treatment of high risk soft tissue sarcoma: +11.4% 5 yrs. overall survival (OS) and for ovarian cancer with peritoneal involvement nearly +12 months OS gain. As a result interest in combining chemotherapy with hyperthermia, i.e. thermochemotherapy, is growing. Extensive biological research has revealed that hyperthermia causes multiple effects, from direct cell kill to improved oxygenation, whereby each effect has a specific temperature range. Thermal sensitization of the tumor cell for chemotherapy occurs for many drugs at temperatures ranging from 40 to 42 °C with little additional increase of sensitization at higher temperatures. Increasing perfusion/oxygenation and increased extravasation are two other important hyperthermia induced mechanisms. The combination of free drug and hyperthermia has not been found to increase tumor drug concentration. Hence, enhanced effectiveness of free drug will depend on the thermal sensitization of the tumor cells for the applied drug. In contrast to free drugs, experimental animal studies combining hyperthermia and thermo-sensitive liposomal (TSL) drugs delivery have demonstrated to result in a substantial increase of the drug concentration in the tumor. For TSL based chemotherapy, hyperthermia is critical to both increase perfusion and extravasation as well as to trigger TSL drug release, whereby the temperature controlled induction of a local high drug concentration in a highly permeable vessel is driving the enhanced drug uptake in the tumor. Increased drug concentrations up to 26 times have been reported in rodents. Good control of the tissue temperature is required to keep temperatures below 43 °C to prevent vascular stasis. Further, careful timing of the drug application relative to the start of heating is required to benefit optimal from the combined treatment. From the available experimental data it follows that irrespective whether chemotherapy is applied as free drug or using a thermal sensitive liposomal carrier, the optimal thermal dose for thermochemotherapy should be 40-42 °C for 30-60 min, i.e. equivalent to a CEM43 of 1-15 min. Timing is critical: most free drug should be applied simultaneous with heating, whereas TSL drugs should be applied 20-30 min after the start of hyperthermia.

Hyperthermia and smart drug delivery systems for solid tumor therapy.

Chemotherapy is a cornerstone of cancer therapy. Irrespective of the administered drug, it is crucial that adequate drug amounts reach all cancer cells. To achieve this, drugs first need to be absorbed, then enter the blood circulation, diffuse into the tumor interstitial space and finally reach the tumor cells. Next to chemoresistance, one of the most important factors for effective chemotherapy is adequate tumor drug uptake and penetration. Unfortunately, most chemotherapeutic agents do not have favorable properties. These compounds are cleared rapidly, distribute throughout all tissues in the body, with only low tumor drug uptake that is heterogeneously distributed within the tumor. Moreover, the typical microenvironment of solid cancers provides additional hurdles for drug delivery, such as heterogeneous vascular density and perfusion, high interstitial fluid pressure, and abundant stroma. The hope was that nanotechnology will solve most, if not all, of these drug delivery barriers. However, in spite of advances and decades of nanoparticle development, results are unsatisfactory. One promising recent development are nanoparticles which can be steered, and release content triggered by internal or external signals. Here we discuss these so-called smart drug delivery systems in cancer therapy with emphasis on mild hyperthermia as a trigger signal for drug delivery.

Quality assurance guidelines for interstitial hyperthermia.

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical hyperthermia treatments and trials. This document outlines the clinical and technical consequences of the specific properties of interstitial heat delivery and specifies recommendations for hyperthermia administration with interstitial techniques. Interstitial hyperthermia aims at tumor temperatures in the 40-44 °C range as an adjunct to radiation or chemotherapy. The clinical part of this document imparts specific clinical experience of interstitial heat delivery to various tumor sites as well as recommended interstitial hyperthermia workflow and procedures. The second part describes technical requirements for quality assurance of current interstitial heating equipment including electromagnetic (radiative and capacitive) and ultrasound heating techniques. Detailed instructions are provided on characterization and documentation of the performance of interstitial hyperthermia applicators to achieve reproducible hyperthermia treatments of uniform high quality. Output power and consequent temperature rise are the key parameters for characterization of applicator performance in these QA guidelines. These characteristics determine the specific maximum tumor size and depth that can be heated adequately. The guidelines were developed by the ESHO Technical Committee with participation of senior STM members and members of the Atzelsberg Circle.

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.

Current state of the art of regional hyperthermia treatment planning: a review.

Locoregional hyperthermia, i.e. increasing the tumor temperature to 40-45 °C using an external heating device, is a very effective radio and chemosensitizer, which significantly improves clinical outcome. There is a clear thermal dose-effect relation, but the pursued optimal thermal dose of 43 °C for 1 h can often not be realized due to treatment limiting hot spots in normal tissue. Modern heating devices have a large number of independent antennas, which provides flexible power steering to optimize tumor heating and minimize hot spots, but manual selection of optimal settings is difficult. Treatment planning is a very valuable tool to improve locoregional heating. This paper reviews the developments in treatment planning software for tissue segmentation, electromagnetic field calculations, thermal modeling and optimization techniques. Over the last decade, simulation tools have become more advanced. On-line use has become possible by implementing algorithms on the graphical processing unit, which allows real-time computations. The number of applications using treatment planning is increasing rapidly and moving on from retrospective analyses towards assisting prospective clinical treatment strategies. Some clinically relevant applications will be discussed.

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.

Effect of a combined surgery, re-irradiation and hyperthermia therapy on local control rate in radio-induced angiosarcoma of the chest wall.

PURPOSE: Radiation-induced angiosarcoma (RAS) of the chest wall/breast has a poor prognosis due to the high percentage of local failures. The efficacy and side effects of re-irradiation plus hyperthermia (reRT + HT) treatment alone or in combination with surgery were assessed in RAS patients. PATIENTS AND METHODS: RAS was diagnosed in 23 breast cancer patients and 1 patient with melanoma. These patients had previously undergone breast conserving therapy (BCT, n = 18), mastectomy with irradiation (n=5) or axillary lymph node dissection with irradiation (n = 1). Treatment consisted of surgery followed by reRT + HT (n = 8), reRT + HT followed by surgery (n = 3) or reRT + HT alone (n = 13). Patients received a mean radiation dose of 35 Gy (32-54 Gy) and 3-6 hyperthermia treatments (mean 4). Hyperthermia was given once or twice a week following radiotherapy (RT). RESULTS: The median latency interval between previous radiation and diagnosis of RAS was 106 months (range 45-212 months). Following reRT + HT, the complete response (CR) rate was 56 %. In the subgroup of patients receiving surgery, the 3-month, 1- and 3-year actuarial local control (LC) rates were 91, 46 and 46 %, respectively. In the subgroup of patients without surgery, the rates were 54, 32 and 22 %, respectively. Late grade 4 RT toxicity was seen in 2 patients. CONCLUSION: The present study shows that reRT + HT treatment--either alone or combined with surgery--improves LC rates in patients with RAS.

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.

Optimizing deep hyperthermia treatments: are locations of patient pain complaints correlated with modelled SAR peak locations?

During deep hyperthermia treatment, patient pain complaints due to heating are common when maximizing power. Hence, there exists a good rationale to investigate whether the locations of predicted SAR peaks by hyperthermia treatment planning (HTP) are correlated with the locations of patient pain during treatment. A retrospective analysis was performed, using the treatment reports of 35 patients treated with deep hyperthermia controlled by extensive treatment planning. For various SAR indicators, the average distance from a SAR peak to a patient discomfort location was calculated, for each complaint. The investigated V(0.1 closest) (i.e. the part of the 0.1th SAR percentile closest to the patient complaint) performed the best, and leads to an average distance between the SAR peak and the complaint location of 3.9 cm. Other SAR indicators produced average distances that were all above 10 cm. Further, the predicted SAR peak location with V(0.1) provides a 77% match with the region of complaint. The current study demonstrates that HTP is able to provide a global indication of the regions where hotspots during treatment will most likely occur. Further development of this technology is necessary in order to use HTP as a valuable toll for objective and advanced SAR steering. The latter is especially valid for applications that enable 3D SAR steering.

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.

A literature survey on indicators for characterisation and optimisation of SAR distributions in deep hyperthermia, a plea for standardisation.

PURPOSE: To evaluate the predictive value of SAR indicators by assessing the correlation of a SAR indicator with the corresponding predicted temperature. Ultimately, this should lead to a number of verified SAR indicators for characterization and optimization of a predicted SAR distribution. METHODS: A literature survey is followed by an evaluation of the SAR indicators on their functionality, using a set of heuristic classification criteria. To obtain an objective assessment of the predictive value for SAR characterisation, all SAR indicators are evaluated by correlating the value of the SAR indicator to the predicted target temperature when heated with the BSD2000 Sigma 60 applicator. Two methods were followed. First, the specificity of the SAR indicator to target temperature was assessed for each of the 36 patient-specific models, using 30 randomly chosen phase and amplitude settings. Secondly, each SAR indicator was used as a goal function to assess its suitability for optimisation purposes. RESULTS: Only a selected number of SAR indicators correlate well with tumour/target-temperature. Hence, for target-related properties, an adequate set of SAR indicators is found in the literature. For hotspots, modifications are desirable. For optimisation purposes, improved objective functions have been defined. CONCLUSIONS: From the correlation of the SAR indicators with tumour temperature, a preferred set of SAR indicators is derived: For target heating, 'average SAR ratio', 'Hotspot-target SAR ratio', and 'homogeneity coefficient' provide suitable objective criteria, while for hotspot reduction, 'Hotspot-target SAR ratio' is considered the most useful indicator. For optimisation procedures, 'Hotspot-target SAR ratio' is currently the most suitable objective function.

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.