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.

Catheter-based ultrasound applicators for selective thermal ablation: progress towards MRI-guided applications in prostate.

High-temperature thermal therapy is emerging as a feasible treatment option for prostate cancer and benign prostatic hyperplasia. Previous investigations have demonstrated distinct advantages of catheter-based ultrasound technology over other heating modalities for thermal ablation therapies, with significant potential for better spatial control and faster heating times. The purpose of this study was to develop ultrasound devices and techniques specifically for treating prostate cancer in conjunction with magnetic resonance thermal imaging (MRTI) to monitor and control treatment progression. Directional transurethral applicators have been designed with arrays of sectored tubular (90 degrees active acoustic sector) or with narrow planar transducer segments and integrated with a flexible delivery catheter with a cooling balloon. This applicator can be rotated within the prostatic urethra to target specific regions during treatment. MRI compatible catheter-cooled interstitial ultrasound applicators with 180 degrees active acoustic sectors were developed specifically to treat the prostate. These applicators may be implanted through the perineum into the posterior portion of the prostate, with their heating energy directed away from the rectum. Both heating strategies were evaluated via biothermal simulations and in vivo experiments within canine prostate (n = 3). During the in vivo studies, MRTI was used to monitor treatment temperatures, cytotoxic thermal doses (t43 > 240 min) and corresponding maximum temperature thresholds (Tmax > 52 degrees C) within three imaging planes simultaneously. Urethral and endorectal cooling was employed with both treatment strategies to provide further protection of the urethral mucosa and rectum from thermal damage. Results using the transurethral applicators demonstrated that narrow zones of coagulation (approximately 30 degrees sector for planar, approximately 90 degrees for tubular), extending up to 20 mm from the urethra to the periphery of the prostate gland, could be produced within 10-15 min. Further, rotation of the applicator during treatment could be used to destroy larger regions in the prostate. Experiments using multiple interstitial directional applicators (approximately 180 degrees active sectors), implanted within the posterior margin of the prostate with the energy directed away from the rectum, produced contiguous zones of thermal coagulation which extended from the posterior prostate toward the anterior-lateral periphery of the gland. Both transurethral and interstitial treatment strategies demonstrated significant potential for thermal ablation of localized prostate cancer, particularly when MRTI is used to guide and assess treatment.

Control of interstitial thermal coagulation: comparative evaluation of microwave and ultrasound applicators.

This study presents a comparative evaluation of the control of heating and thermal coagulation with microwave (MW) and ultrasound (US) interstitial applicators. Helical coil MW antennas (17 mm and 25 mm length radiating antennae) were tested using an external implant catheter (2.2 mm o.d.) with water-cooling. US applicators with tubular transducers (2.2 and 2.5 mm o.d., 10 mm length, single-element and 3-element) were utilized with a direct-coupled configuration and internal water-cooling. Measurements of E-field distributions (for MW) and acoustic beam distributions (for US) were used to characterize the applicator energy output. Thermal performance was evaluated through multiple heating trials in vitro (bovine liver) and in vivo (porcine thigh muscle and liver) at varied levels of applied power (20-40 W for microwave, 15-35 W for ultrasound) and heating times (0.5-5 min). Axial temperature distributions in the tissue were recorded during heating, and dimensions of the resulting lesions of thermal coagulation were measured. Both MW and US applicators produced large volumes of tissue coagulation ranging from 8 to 20 cm3 with singular heating times of 5 min. Radial depth of lesions for both MW and US applicators increased with heating duration and power levels, though US produced notably larger lesion diameters (30-42 mm for US vs 18-26 mm for MW, 5 min heating). Characteristic differences between the applicators were observed in axial energy distribution, tissue temperatures, and thermal lesion shapes. MW lesions increased significantly in axial dimensions (beyond the active applicator length) as applied power level and/or heating duration was increased, and lesion shapes were generally not uniform. US provided greater control and uniformity of heating, with energy deposition and axial extent of thermal lesions corresponding to the length of the active transducer(s). The improved ability to control the extent of thermal coagulation demonstrated by the US applicators provides greater potential to target a specific region of tissue.

Combination of transurethral and interstitial ultrasound applicators for high-temperature prostate thermal therapy.

The purpose of this study was to determine the feasibility of using a transurethral ultrasound applicator in combination with implantable ultrasound applicators for inducing thermal coagulation and necrosis of localized cancer lesions or benign disease within the prostate gland. The potential to treat target zones in the anterior and lateral portions of the prostate with the angularly directive transurethral applicator, while simultaneously treating regions of extracapsular extension and zones in the posterior prostate with the directive implantable applicators in combination with a rectal cooling bolus, is evaluated. Biothermal computer simulations, acoustic characterizations, and in vivo thermal dosimetry experiments with canine prostates were used to evaluate the performance of each applicator type and combinations thereof. Simulations have demonstrated that transurethral applicators with 180-270 degrees acoustic active zones can direct therapeutic heating patterns to the anterior and lateral prostate, implantable needles can isolate heating to the posterior gland while avoiding rectal tissue, and that the combination of applicators can be used to produce conformal heating to the whole gland. Single implantable applicators (1.8 mm OD x 10 mm long, approximately 180 degrees active sector, approximately 7 MHz, direct-coupled type) produced directional thermal lesions within in vivo prostate, with temperatures >50 degrees C extending more than 10 mm radially after 10-15 min. Combination of interstitial applicators (1-2) and a transurethral applicator (3-2.5 mm OD x 6 mm long, approximately 180 degrees active sector, 6.8 MHz, 6 mm OD delivery catheter) produced conforming temperature distributions (48-85 degrees C) and zones of acute thermal damage within 15 min. The preliminary results of this investigation demonstrate that implantable directional ultrasound applicators, in combination with a transurethral ultrasound applicator, have the potential to provide thermal coagulation and necrosis of small or large regions within the prostate gland, while sparing thermally sensitive rectal tissue.

Thermal and SAR characterization of multielement dual concentric conductor microwave applicators for hyperthermia, a theoretical investigation.

Six aperture array dual concentric conductor (DCO) microwave hyperthermia applicators were studied using theoretical models to characterize power deposition (SAR) and steady state temperature distributions in perfused tissue. SAR patterns were calculated using the finite difference time domain (FDTD) numerical method, and were used as input to a finite difference thermal modeling program based on the Pennes Bio-Heat Equation in order to calculate corresponding temperature distributions. Numerous array configurations were investigated including the use of different size DCC apertures (2, 3, and 4 cm), different spacing between apertures (1.0-2.0 cm), and different water bolus thicknesses (5-15 mm). Thermal simulations were repeated using blood perfusion values ranging from 0.5 to 5 kg/m3 s. Results demonstrate the ability of DCC array applicators to effectively and uniformly heat tissue down to a depth of 7.5-10 mm below the skin surface for a large number of different combinations of DCC element size, spacing, and water bolus thickness. Results also reveal the close correlation between SAR patterns and corresponding temperature distributions, verifying that design studies of the applicator can be performed confidently by analysis of SAR, from which the thermal behavior can be estimated. These simulations are useful in the design optimization of large microwave DCC array applicators for superficial tissue heating and for identifying appropriate aperture spacing and bolus thickness parameters for different size DCC aperture arrays and tissue blood perfusion conditions.

Directional power deposition from direct-coupled and catheter-cooled interstitial ultrasound applicators.

This research represents an experimental investigation of the directional power deposition capabilities of interstitial ultrasound applicators intended for applications in hyperthermia and thermal surgery for cancerous or benign disease. Direct-coupled and catheter-cooled ultrasound applicators were fabricated using cylindrical piezoceramic transducers sectored to produce 90 degrees, 180 degrees or 270 degrees active acoustic zones. The applicators were characterized through measurements of acoustic power output and intensity beam distributions in degassed water, in vitro temperature measurements in a perfused kidney model, and in vivo temperature distributions in pig thigh muscle. The angular power deposition patterns obtained in water were closely correlated to the resultant temperature distributions measured in the perfused kidney and in vivo pig thigh muscle. These sectored catheter-cooled and direct-coupled devices both demonstrated the ability to generate high temperatures (>50 degrees C) at sustained high power output levels (6-12 W) without degradation of the ultrasound transducers. Directional control of the energy deposition from the sectored ultrasound applicators was verified with corresponding temperature profiles in both the in vitro and in vivo experiments, as well as with angularly shaped thermal lesions. This is significant in that it demonstrates that heating in the angular expanse can be controlled with interstitial ultrasound applicators, thus providing more conformal thermal therapy by directing the thermal energy in the targeted tissue while protecting non-targeted tissue from thermal damage.

Ultrasound technology for hyperthermia.

Hyperthermia (HT) is used in the clinical management of cancer and benign disease. Numerous biological and clinical investigations have demonstrated that HT in the 41-45 degrees C range can significantly enhance clinical responses to radiation therapy, and has potential for enhancing other therapies, such as chemotherapy, immunotherapy and gene therapy. Furthermore, high-temperature hyperthermia (greater than 50 degrees C) alone is being used for selective tissue destruction as an alternative to conventional invasive surgery. The degree of thermal enhancement of these therapies is strongly dependent on the ability to localize and maintain therapeutic temperature elevations. Due to the often heterogeneous and dynamic properties of tissues, most notably blood perfusion and the presence of thermally significant blood vessels, therapeutic temperature elevations are difficult to spatially and temporally control during these forms of HT therapy. However, ultrasound technology has significant advantages that allow for a higher degree of spatial and dynamic control of the heating compared to other commonly utilized heating modalities. These advantages include a favorable range of energy penetration characteristics in soft tissue and the ability to shape the energy deposition patterns. Thus, heating systems have been developed for interstitial, intracavitary, or external approaches that utilize properties such as multiple transducer arrays, phased arrays, focused beams, mechanical and/or electrical scanning, dynamic frequency control and transducers of various shapes and sizes. This article provides a general review of a selection of ultrasound hyperthermia systems that are either in clinical use or currently under development, that utilize these advantages as a means to better localize and control HT for the aforementioned therapies.

Minimax optimization-based inverse treatment planning for interstitial thermal therapy.

The following work represents the development and evaluation of a minimax optimization-based inverse treatment planning approach for interstitial thermal therapy of cancer and benign disease. The goal is to determine a priori optimal applicator placements and power level settings to maintain the minimum tumour temperature, Tmin, and maximum normal tissue temperature, Tmax within a prescribed therapeutic temperature range. The temperature distribution is approximated by a finite element method (FEM) solution of a bioheat transfer equation on a nonuniform finite element mesh. Lower and upper therapeutic temperature thresholds are specified in the tumour and surrounding normal tissues. A constrained minimax optimization problem is formulated to determine optimal applicator positions and power level settings that minimize the maximum (rather than average) temperature errors in the target tumour region and surrounding normal tissues. The optimization problem is formulated for two general classes of interstitial heating applicators, those with and without a surface cooling mechanism. The viability and sensitivity of this approach is investigated in the two-dimensional setting for various tumour shapes and blood perfusion levels using surface-cooled and direct-coupled interstitial ultrasound applicator power deposition models. These preliminary results indicate the utility of this approach for meeting a prescribed Tmin/Tmax-based clinical objective criterion, and its potential for generating optimal treatment plans that can withstand variations or uncertainty in blood perfusion levels.

Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost +/- hyperthermia for glioblastoma multiforme.

PURPOSE: To determine if adjuvant interstitial hyperthermia (HT) significantly improves survival of patients with glioblastoma undergoing brachytherapy boost after conventional radiotherapy. METHODS AND MATERIALS: Adults with newly-diagnosed, focal, supratentorial glioblastoma < or = 5 cm in diameter were registered postoperatively on a Phase II/III randomized trial and treated with partial brain radiotherapy to 59.4 Gy with oral hydroxyurea. Those patients whose tumor was still implantable after teletherapy were randomized to brachytherapy boost (60 Gy at 0.40-0.60 Gy/h) +/- HT for 30 min immediately before and after brachytherapy. Time to progression (TTP) and survival from date of diagnosis were estimated using the Kaplan-Meier method. RESULTS: From 1990 to 1995, 112 eligible patients were entered in the trial. Patient ages ranged from 21-78 years (median, 54 years) and KPS ranged from 70-100 (median, 90). Most commonly due to tumor progression or patient refusal, 33 patients were never randomized. Of the patients, 39 were randomized to brachytherapy ("no heat") and 40 to brachytherapy + HT ("heat"). By intent to treat, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.04 and p = 0.04). For the 33 "no heat" patients and 35 "heat" patients who underwent brachytherapy boost, TTP and survival were significantly longer for "heat" than "no heat" (p = 0.045 and p = 0.02, respectively; median survival 85 weeks vs. 76 weeks; 2-year survival 31% vs. 15%). A multivariate analysis for these 68 patients adjusting for age and KPS showed that improved survival was significantly associated with randomization to "heat" (p = 0.008; hazard ratio 0.51). There were no Grade 5 toxicities, 2 Grade 4 toxicities (1 on each arm), and 7 Grade 3 toxicities (1 on "no heat" and 6 on the "heat" arm). CONCLUSION: Adjuvant interstitial brain HT, given before and after brachytherapy boost, after conventional radiotherapy significantly improves survival of patients with focal glioblastoma, with acceptable toxicity.

Effect of practical layered dielectric loads on SAR patterns from dual concentric conductor microstrip antennas.

Radiation patterns of 2 and 4cm square Dual Concentric Conductor (DCC) microstrip antennas were studied theoretically with Finite Difference Time Domain (FDTD) analysis and compared with experimental measurements of power deposition (SAR) in layered lossy dielectric loads. Single and array configurations were investigated with 915 MHz excitation applied across either one, two or four sides, or four corners of the square apertures. FDTD simulations were carried out for realistic models of a muscle tissue load coupled to the DCC antennas with a 5 mm thick bolus of either distilled water or low loss Silicone Oil. This study characterizes the effect on SAR of adding three additional thin dielectric layers which are necessary for clinical use of the applicator. These layers consist of a 0.1 mm thick dielectric coating on the array surface to provide electrical isolation of DCC apertures, and 0.15 mm thick plastic layers above and below the bolus to contain the liquid. Experimental measurements of SAR in a plane 1 cm deep in muscle phantom agree well with theoretical FDTD simulations in the multi-layered tissue models. These studies reveal significant changes in SAR for applicator configurations involving low dielectric constant (Er) layers on either side of a high Er water bolus layer. Prominent changes include a broadening and centring of the SAR under each aperture as well as increased SAR penetration in muscle. No significant differences are noted between the simple and complete load configurations for the low Er Silicone Oil bolus. Both theoretical and measured data demonstrate relatively uniform SAR distributions with > 50% of maximum SAR extending to the perimeter of single and multi-aperture array configurations of DCC applicators when using a thin 5 mm water or Silicone Oil bolus.

Ultrasound applicators with integrated catheter-cooling for interstitial hyperthermia: theory and preliminary experiments.

Theoretical and experimental methods were used to evaluate a design of ultrasound applicators for interstitial hyperthermia. The basic schema consists of a multielement array of tubular piezoceramic radiators (1.5-1.6 mm diameter), each 5-10 mm long with separate power control, designed to be inserted within a 13-14 gauge closed-end brachytherapy implant catheter. Channels for circulating temperature-regulated water are integrated within the applicator to provide control of the catheter/tissue interface temperature. A quantitative theoretical analysis was undertaken to determine heating performance as a function of applicator spacing, blood perfusion, catheter material, frequency and required acoustic power output. Prototype multielement applicators were constructed and characterized in terms of acoustic pressure-squared distributions and acoustic power output capabilities. This study demonstrated distinct advantages of these catheter-cooled multielement ultrasound applicators within an implant, including higher T90's achievable within highly perfused tissues, dynamic control of the longitudinal power deposition, and no interaction between adjacent applicators or elements or sensitivity to applicator alignment. Preliminary measurements of prototype devices have indicated that implementation of these interstitial ultrasound applicators with integrated catheter-cooling is practicable, yet further development and in vivo verification of performance is warranted.

An improved bolus configuration for commercial multielement ultrasound and microwave hyperthermia systems.

A simple modification is presented for two commercially available hyperthermia applicators which dramatically improves the regulation and dynamic control of the temperature at the bolus/tissue interface. This alteration requires the addition of a variable speed pump, bubble trap, simple heat exchanger, and a few minor changes to the existing system. With this modified design, the water within the bolus is directly circulated and temperature controlled. The convective nature of the circulating system ensures uniform temperature throughout the extended bolus and increases the thermal energy transfer at the bolus/tissue interface. This modification also provides significantly improved flexibility in controlling the treatment temperature distributions since the bolus/tissue interface temperature can now be dynamically varied during a treatment, in addition to adjusting the applicator power output and frequency.

Pre-clinical evaluation of a microwave planar array applicator for superficial hyperthermia.

Multi-element hyperthermia applicators have an advantage over single-aperture devices in that the power deposition pattern across the applicator surface may be adjusted to improve the resultant temperature distribution. This capability can be used to compensate for irregular tumour geometry as well as heterogeneity of thermal and power absorption parameters within the tissue. This paper evaluates the first commercially available microwave system of this type designed for superficial hyperthermia. The applicator (16-element planar array, 915 MHz, 15.2 x 15.2 cm footprint) was evaluated by the following: (1) measuring absolute SAR distributions in muscle-equivalent liquid phantom with an intervening 1 cm thick layer of fat phantom by scanning a calibrated E-field sensor, and (2) power output measurements using calorimetric methods. The SAR distributions measured for each individual aperture exhibited significant irregularities and differing power deposition patterns. A priori knowledge of these different power deposition characteristics was used to provide appropriate illumination schemes which could be used as initial starting points for producing clinically useful power deposition patterns. Measurements of these composite patterns demonstrate the adjustable nature and flexibility of the heating capabilities of this applicator, which includes 50% iso-SAR coverage that can be extended to the applicator perimeter. This clearly illustrates the clinical utility and potential advantages of this system over single-aperture devices for superficial hyperthermia.

The development of intracavitary ultrasonic applicators for hyperthermia: a design and experimental study.

This study investigated the design concepts and development of a multielement intracavitary ultrasound applicator for use in hyperthermia. A necessary condition imposed on these applicators is that each transducer element be separately powered and produce collimated beams. This way, the power deposition within the target volume can be controlled by varying the power to each element. Theoretical computer simulations (acoustic and thermal) and bench experiments were used to determine the constraints on the transducer element size and the spacing between them. These have shown that the length of the cylindrical segments (or subsections of) must be greater than approximately 10 lambda for proper collimation and that the spacing between them must be less than approximately 1.5 mm for uniform heating. With these design principles in mind, applicators were constructed using sections of cylindrical transducers (wall-thickness resonance). These were surrounded by temperature-controlled circulating water which was enclosed by a latex membrane. This allowed for acoustic coupling and additional control over the depth of the maximum temperature from the cavity wall. This depth could be varied between the cavity surface and up to 1.5 cm for circulating water temperatures between 5 and 42 degrees C, respectively. These applicators were tested in vivo and were able to induce controlled transrectal heating, at depths of 2-3 cm, in the canine rectum and prostate gland.

Induction of hyperthermia using an intracavitary multielement ultrasonic applicator.

In this paper, the possibility of inducing controlled hyperthermia in rectal or vaginal wall tumors using an intracavitary ultrasonic applicator was investigated. A computer model that took into account the thermal and ultrasonic properties of tissues and surface cooling was used to optimize the transducer parameters to obtain desirable temperature distributions for different perfusion situations in the tumor. Also, an applicator that consisted of a cylindrical array of five independently controllable ultrasonic transducers was developed. This array was then tested in degassed water to determine the functional characteristics. This same applicator, modified to include water cooling of the tissue surface, was tested in vivo in dogs. The temperature distributions were found to be promising and with modifications this approach will be used in clinical treatments of suitable tumors.