Quantitative analysis of contribution of mild and moderate hyperthermia to thermal ablation and sensitization of irreversible electroporation of pancreatic cancer cells.

INTRODUCTION: Irreversible electroporation (IRE) is an ablation modality that applies short, high-voltage electric pulses to unresectable cancers. Although considered a non-thermal technique, temperatures do increase during IRE. This temperature rise sensitizes tumor cells for electroporation as well as inducing partial direct thermal ablation. AIM: To evaluate the extent to which mild and moderate hyperthermia enhance electroporation effects, and to establish and validate in a pilot study cell viability models (CVM) as function of both electroporation parameters and temperature in a relevant pancreatic cancer cell line. METHODS: Several IRE-protocols were applied at different well-controlled temperature levels (37 °C ≤ T ≤ 46 °C) to evaluate temperature dependent cell viability at enhanced temperatures in comparison to cell viability at T = 37 °C. A realistic sigmoid CVM function was used based on thermal damage probability with Arrhenius Equation and cumulative equivalent minutes at 43 °C (CEM43°C) as arguments, and fitted to the experimental data using "Non-linear-least-squares"-analysis. RESULTS: Mild (40 °C) and moderate (46 °C) hyperthermic temperatures boosted cell ablation with up to 30% and 95%, respectively, mainly around the IRE threshold Eth,50% electric-field strength that results in 50% cell viability. The CVM was successfully fitted to the experimental data. CONCLUSION: Both mild- and moderate hyperthermia significantly boost the electroporation effect at electric-field strengths neighboring Eth,50%. Inclusion of temperature in the newly developed CVM correctly predicted both temperature-dependent cell viability and thermal ablation for pancreatic cancer cells exposed to a relevant range of electric-field strengths/pulse parameters and mild moderate hyperthermic temperatures.

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.

Validation and practical use of Plan2Heat hyperthermia treatment planning for capacitive heating.

BACKGROUND: Capacitive devices are used for hyperthermia delivery, initially mainly in Asia, but nowadays also increasingly in Europe. Treatment planning can be very useful to determine the most effective patient-specific treatment set-up. This paper provides a validation of GPU-based simulations using Plan2Heat for capacitive hyperthermia devices. METHODS: Validation was first performed by comparing simulations with an analytical solution for a spherical object placed inside a uniform electric field. Resolution was 5, 2.5 or 1 mm. Next, simulations for homogeneous and inhomogeneous phantom setups were performed for Thermotron RF8 and Celsius TCS capacitive heating devices at 2.5 mm resolution. Also different combinations of electrode sizes were evaluated. Normalized SAR profiles were compared to phantom measurements from the literature. Possible clinical use of treatment planning was demonstrated for an anal cancer patient, evaluating different treatment set-ups in prone and supine position. RESULTS: Numerical and analytical solutions showed excellent agreement. At the center of the sphere, the error was 5.1%, 2.9% and 0.2% for a resolution of 5, 2.5 and 1 mm, respectively. Comparison of measurements and simulations for both Thermotron RF8 and Celsius TCS showed very good agreement within 5% for all phantom set-ups. Simulations were capable of accurately predicting the penetration depth; a very relevant parameter for clinical application. The patient case illustrated that planning can provide insight by comparing effectiveness of different treatment strategies. CONCLUSION: Plan2Heat can rapidly and accurately predict heating patterns generated by capacitive devices. Thus, Plan2Heat is suitable for patient-specific treatment planning for capacitive hyperthermia.

Treatment planning facilitates clinical decision making for hyperthermia treatments.

Background: Treatment quality is important in clinical hyperthermia. Guideline-based treatment protocols are used to determine system settings and treatment strategies to ensure effective tumor heating and prevent unwanted treatment-limiting normal tissue hot spots. Realizing both these goals can prove challenging using generic guideline-based and operator-dependent treatment strategies. Hyperthermia treatment planning (HTP) can be very useful to support treatment strategies. Although HTP is increasingly integrated into the standard clinical workflow, active clinical application is still limited to a small number of hyperthermia centers and should be further stimulated.Purpose: This paper aims to serve as a practical guide, demonstrating how HTP can be applied in clinical decision making for both superficial and locoregional hyperthermia treatments.HTP in clinical decision making: Seven problems that occur in daily clinical practice are described and we show how HTP can enhance insight to formulate an adequate treatment strategy. Examples use representative commercially available hyperthermia devices and cover all stages during the clinical workflow. Problems include selecting adequate phase settings, heating ability analysis, hot spot suppression, applicator selection, evaluation of target coverage and heating depth, and predicting possible thermal toxicity in case of an implant. Since we aim to promote a general use of HTP in daily practice, basic simulation strategies are used in these problems, avoiding a need for the application of dedicated advanced optimization routines that are not generally available.Conclusion: Even fairly basic HTP can facilitate clinical decision making, providing a meaningful and clinically relevant contribution to maintaining and improving treatment quality.

Molecular and biological rationale of hyperthermia as radio- and chemosensitizer.

Mild hyperthermia, local heating of the tumour up to temperatures <43 °C, has been clinically applied for almost four decades and has been proven to substantially enhance the effectiveness of both radiotherapy and chemotherapy in treatment of primary and recurrent tumours. Clinical results and mechanisms of action are discussed in this review, including the molecular and biological rationale of hyperthermia as radio- and chemosensitizer as established in in vitro and in vivo experiments. Proven mechanisms include inhibition of different DNA repair processes, (in)direct reduction of the hypoxic tumour cell fraction, enhanced drug uptake, increased perfusion and oxygen levels. All mechanisms show different dose effect relationships and different optimal scheduling with radiotherapy and chemotherapy. Therefore, obtaining the ideal multi-modality treatment still requires elucidation of more detailed data on dose, sequence, duration, and possible synergisms between modalities. A multidisciplinary approach with different modalities including hyperthermia might further increase anti-tumour effects and diminish normal tissue damage.

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 effect of air pockets in the urinary bladder on the temperature distribution during loco-regional hyperthermia treatment of bladder cancer patients.

PURPOSE: Loco-regional hyperthermia combined with mitomycin C is used for treatment of nonmuscle invasive bladder cancer (NMIBC). Air pockets may be present in the bladder during treatment. The aim of this study is to quantify the effect of air pockets on the thermal dose of the bladder. METHODS: We analysed 16 patients treated for NMIBC. Loco-regional hyperthermia was performed with the in-house developed 70 MHz AMC-4 hyperthermia device. We simulated treatments with the clinically applied device settings using Plan2Heat (developed in-house) including the air pockets delineated on CT scans made following treatment, and with the same volume filled with urine. Temperature distributions simulated with and without air pockets were compared. RESULTS: The average air and fluid volumes in the bladder were 6.0 ml (range 0.8 - 19.3 ml) and 183 ml (range 47-322 ml), respectively. The effect of these air pockets varied strongly between patients. Averaged over all patients, the median bladder wall temperature (T50) remained unchanged when an air pocket was present. Temperature changes exceeded ±0.2 °C in, on average, 23% of the bladder wall volume (range 1.3-59%), in 6.0% (range 0.6-20%) changes exceeded ±0.5 °C and in 3.2% (range 0.0-7.4%) changes exceeded ±1.0 °C. There was no correlation between the differences in temperature and the air pocket or bladder volume. There was a positive correlation between air pocket surface and temperature heterogeneity. CONCLUSION: Presence of air causes more heterogeneous bladder wall temperatures and lower T90, particularly for larger air pockets. The size of air pockets must therefore be minimized during bladder hyperthermia treatments.

Predictive value of simulated SAR and temperature for changes in measured temperature after phase-amplitude steering during locoregional hyperthermia treatments.

INTRODUCTION: On-line adaptive hyperthermia treatment planning can be useful to suppress treatment limiting hot spots and improve tumor temperatures during locoregional hyperthermia. This requires adequate prediction of changes in heating patterns after phase-amplitude steering. We investigated the predictive value of simulated SAR and temperature for changes in measured temperature after phase-amplitude steering during locoregional hyperthermia. METHODS: All treatment sessions of 75 patients with pelvic malignancies treated between September 2013 and March 2018 were evaluated. Phase-amplitude adaptations during the 60 min steady-state period were analyzed. Treatment planning was performed using Plan2Heat, based on CT scans with (thermometry) catheters in the vagina, rectum, and bladder in situ. The predicted SAR and temperature along the thermometry tracks were extracted from the simulated distributions. Correlations between changes in average measured temperature and the simulated SAR and temperature were evaluated for single phase-amplitude steering events, unaccompanied by other (steering) actions. RESULTS: A total of 67 phase-amplitude steering events were suitable for analysis. Simulated changes in both SAR and temperature correlated with the measured temperature changes. For the vagina, R2 = 0.44 and R2 = 0.55 for SAR and temperature, respectively. For the rectum, these values were 0.53 for SAR and 0.66 for temperature. Correlations for the bladder were weaker: R2 = 0.15 and R2 = 0.14 for SAR and temperature, respectively. This can be explained by convection in the bladder fluid, unaccounted for by present treatment planning. CONCLUSION: Treatment planning can predict changes in an average temperature after phase-amplitude steering. This allows on-line support with phase-amplitude steering to optimize hyperthermia treatments.

The effect of time interval between radiotherapy and hyperthermia on planned equivalent radiation dose.

PURPOSE: Thermoradiotherapy is an effective treatment for locally advanced cervical cancer. However, the optimal time interval between radiotherapy and hyperthermia, resulting in the highest therapeutic gain, remains unclear. This study aims to evaluate the effect of time interval on the therapeutic gain using biological treatment planning. METHODS: Radiotherapy and hyperthermia treatment plans were created for 15 cervical cancer patients. Biological modeling was used to calculate the equivalent radiation dose, that is, the radiation dose that results in the same biological effect as the thermoradiotherapy treatment, for different time intervals ranging from 0-4 h. Subsequently, the thermal enhancement ratio (TER, i.e. the ratio of the dose for the thermoradiotherapy and the radiotherapy-only plan) was calculated for the gross tumor volume (GTV) and the organs at risk (OARs: bladder, rectum, bowel), for each time interval. Finally, the therapeutic gain factor (TGF, i.e. TERGTV/TEROAR) was calculated for each OAR. RESULTS: The median TERGTV ranged from 1.05 to 1.16 for 4 h and 0 h time interval, respectively. Similarly, for bladder, rectum and bowel, TEROARs ranged from 1-1.03, 1-1.04 and 1-1.03, respectively. Radiosensitization in the OARs was much less than in the GTV, because temperatures were lower, fractionation sensitivity was higher (lower α/ß) and direct cytotoxicity was assumed negligible in normal tissue. TGFs for the three OARs were similar, and were highest (around 1.12) at 0 h time interval. CONCLUSION: This planning study indicates that the largest therapeutic gain for thermoradiotherapy in cervical cancer patients can be obtained when hyperthermia is delivered immediately before or after radiotherapy.

Locoregional hyperthermia of deep-seated tumours applied with capacitive and radiative systems: a simulation study.

BACKGROUND: Locoregional hyperthermia is applied to deep-seated tumours in the pelvic region. Two very different heating techniques are often applied: capacitive and radiative heating. In this paper, numerical simulations are applied to compare the performance of both techniques in heating of deep-seated tumours. METHODS: Phantom simulations were performed for small (30 × 20 × 50 cm3) and large (45 × 30 × 50 cm3), homogeneous fatless and inhomogeneous fat-muscle, tissue-equivalent phantoms with a central or eccentric target region. Radiative heating was simulated with the 70 MHz AMC-4 system and capacitive heating was simulated at 13.56 MHz. Simulations were performed for small fatless, small (i.e. fat layer typically <2 cm) and large (i.e. fat layer typically >3 cm) patients with cervix, prostate, bladder and rectum cancer. Temperature distributions were simulated using constant hyperthermic-level perfusion values with tissue constraints of 44 °C and compared for both heating techniques. RESULTS: For the small homogeneous phantom, similar target heating was predicted with radiative and capacitive heating. For the large homogeneous phantom, most effective target heating was predicted with capacitive heating. For inhomogeneous phantoms, hot spots in the fat layer limit adequate capacitive heating, and simulated target temperatures with radiative heating were 2-4 °C higher. Patient simulations predicted therapeutic target temperatures with capacitive heating for fatless patients, but radiative heating was more robust for all tumour sites and patient sizes, yielding target temperatures 1-3 °C higher than those predicted for capacitive heating. CONCLUSION: Generally, radiative locoregional heating yields more favourable simulated temperature distributions for deep-seated pelvic tumours, compared with capacitive heating. Therapeutic temperatures are predicted for capacitive heating in patients with (almost) no fat.

Feasibility of on-line temperature-based hyperthermia treatment planning to improve tumour temperatures during locoregional hyperthermia.

BACKGROUND: The effectiveness of hyperthermia is strongly dependent on the achieved tumour temperatures. Phased-array systems allow flexible power steering to realise good tumour heating while avoiding excessive heating in normal tissue, but the limited quantitative accuracy of pre-treatment planning complicates realising optimal tumour heating. On-line hyperthermia treatment planning could help to improve the heating quality. This paper demonstrates the feasibility of using on-line temperature-based treatment planning to improve the heating quality during hyperthermia in three patients. METHODS: Hyperthermia treatment planning was performed using the Plan2Heat software package combined with a dedicated graphical user interface for on-line application. Electric fields were pre-calculated to allow instant update and visualisation of the predicted temperature distribution for user-selected phase-amplitude settings during treatment. On-line treatment planning using manual variation of system settings for the AMC-8 hyperthermia system was applied in one patient with a deep-seated pelvic melanoma metastasis and two cervical cancer patients. For a clinically relevant improvement the increase in average target temperature should be at least 0.2 °C. RESULTS: With the assistance of on-line treatment planning a substantial improvement in tumour temperatures was realised for all three patients. In the melanoma patient, the average measured target temperature increased from 38.30 °C to 39.15 °C (i.e. +0.85 °C). In the cervical cancer patients, the average measured target temperature increased from 41.30 °C to 42.05 °C (i.e. +0.75 °C) and from 41.70 °C to 42.80 °C (i.e. +1.1 °C), respectively. CONCLUSION: On-line temperature-based treatment planning is clinically feasible to improve tumour temperatures. A next, worthwhile step is automatic optimisation for a larger number of patients.

Planning, optimisation and evaluation of hyperthermia treatments.

BACKGROUND: Hyperthermia treatment planning using dedicated simulations of power and temperature distributions is very useful to assist in hyperthermia applications. This paper describes an advanced treatment planning software package for a wide variety of applications. METHODS: The in-house developed C++ software package Plan2Heat runs on a Linux operating system. Modules are available to perform electric field and temperature calculations for many heating techniques. The package also contains optimisation routines, post-treatment evaluation tools and a sophisticated thermal model enabling to account for 3D vasculature based on an angiogram or generated artificially using a vessel generation algorithm. The use of the software is illustrated by a simulation of a locoregional hyperthermia treatment for a pancreatic cancer patient and a spherical tumour model heated by interstitial hyperthermia, with detailed 3D vasculature included. RESULTS: The module-based set-up makes the software flexible and easy to use. The first example demonstrates that treatment planning can help to focus the heating to the tumour. After optimisation, the simulated absorbed power in the tumour increased with 50%. The second example demonstrates the impact of accurately modelling discrete vasculature. Blood at body core temperature entering the heated volume causes relatively cold tracks in the heated volume, where the temperature remains below 40 °C. CONCLUSIONS: A flexible software package for hyperthermia treatment planning has been developed, which can be very useful in many hyperthermia applications. The object-oriented structure of the source code allows relatively easy extension of the software package with additional tools when necessary for future applications.

Improving hyperthermia treatment planning for the pelvis by accurate fluid modeling.

PURPOSE: Hyperthermia is an established (neo)adjuvant treatment modality for a number of pelvic malignancies. Optimal treatment of these tumors requires robust treatment planning, but up until now, the urinary bladder was not modeled accurately, making current simulations less reliable. The authors improved the dielectric and thermophysical model of the urinary bladder in their treatment planning system, and showed the improvements using phantom experiments. METHODS: The authors suspended a porcine bladder in muscle tissue equivalent gel and filled it with 120 ml 0.9% saline. The authors heated the phantom during 15 min with their deep hyperthermia device, using clinical settings, and measured the temperature both inside and outside the bladder. The authors simulated the experiment, both using the clinically used treatment planning system, and using the improved model featuring correct dielectric properties for the bladder content and an enhanced thermophysical model, enabling the simulation of convection. RESULTS: Although the dielectric changes have an impact throughout the phantom, the dominant effect is a higher net heat absorption in the bladder. The effects of changing the thermophysical model are limited to the bladder and its surroundings, but result in a very different temperature profile. The temperatures predicted by the simulations using the new bladder model were in much better agreement with the measurements than those predicted by currently used treatment planning system. CONCLUSIONS: Modeling convection in the urinary bladder is very important for accurate hyperthermia treatment planning in the pelvic area.

Biological modelling of the radiation dose escalation effect of regional hyperthermia in cervical cancer.

BACKGROUND: Locoregional hyperthermia combined with radiotherapy significantly improves locoregional control and overall survival for cervical tumors compared to radiotherapy alone. In this study biological modelling is applied to quantify the effect of radiosensitization for three cervical cancer patients to evaluate the improvement in equivalent dose for the combination treatment with radiotherapy and hyperthermia. METHODS: The Linear-Quadratic (LQ) model extended with temperature-dependent LQ-parameters α and ß was used to model radiosensitization by hyperthermia and to calculate the conventional radiation dose that is equivalent in biological effect to the combined radiotherapy and hyperthermia treatment. External beam radiotherapy planning was performed based on a prescription dose of 46Gy in 23 fractions of 2Gy. Hyperthermia treatment using the AMC-4 system was simulated based on the actual optimized system settings used during treatment. RESULTS: The simulated hyperthermia treatments for the 3 patients yielded a T50 of 40.1 °C, 40.5 °C, 41.1 °C and a T90 of 39.2 °C, 39.7 °C, 40.4 °C, respectively. The combined radiotherapy and hyperthermia treatment resulted in a D95 of 52.5Gy, 55.5Gy, 56.9Gy in the GTV, a dose escalation of 7.3-11.9Gy compared to radiotherapy alone (D95 = 45.0-45.5Gy). CONCLUSIONS: This study applied biological modelling to evaluate radiosensitization by hyperthermia as a radiation-dose escalation for cervical cancer patients. This model is very useful to compare the effectiveness of different treatment schedules for combined radiotherapy and hyperthermia treatments and to guide the design of clinical studies on dose escalation using hyperthermia in a multi-modality setting.

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.

Fast thermal simulations and temperature optimization for hyperthermia treatment planning, including realistic 3D vessel networks.

PURPOSE: Accurate thermal simulations in hyperthermia treatment planning require discrete modeling of large blood vessels. The very long computation time of the finite difference based DIscrete VAsculature model (DIVA) developed for this purpose is impractical for clinical applications. In this work, a fast steady-state thermal solver was developed for simulations with realistic 3D vessel networks. Additionally, an efficient temperature-based optimization method including the thermal effect of discrete vasculature was developed. METHODS: The steady-state energy balance for vasculature and tissue was described by a linear system, which was solved with an iterative method on the graphical processing unit. Temperature calculations during optimization were performed by superposition of several precomputed temperature distributions, calculated with the developed thermal solver. The thermal solver and optimization were applied to a human anatomy, with the prostate being the target region, heated with the eight waveguide 70 MHz AMC-8 system. Realistic 3D pelvic vasculature was obtained from angiography. Both the arterial and venous vessel networks consisted of 174 segments and 93 endpoints with a diameter of 1.2 mm. RESULTS: Calculation of the steady-state temperature distribution lasted about 3.3 h with the original DIVA model, while the newly developed method took only ≈ 1-1.5 min. Temperature-based optimization with and without taking the vasculature into account showed differences in optimized waveguide power of more than a factor 2 and optimized tumor T90 differed up to ≈ 0.5°C. This shows the necessity to take discrete vasculature into account during optimization. CONCLUSIONS: A very fast method was developed for thermal simulations with realistic 3D vessel networks. The short simulation time allows online calculations and makes temperature optimization with realistic vasculature feasible, which is an important step forward in hyperthermia treatment planning.

Uncertainty in hyperthermia treatment planning: the need for robust system design.

Hyperthermia treatment planning (HTP) is an important tool to improve the quality of hyperthermia treatment. It is a practical way of designing new hyperthermia systems and can be used to optimize the phase and amplitude settings to achieve optimal heating. One of the main challenges to be dealt with however is the uncertainty in the modeling parameters. The role of dielectric and combined dielectric and perfusion uncertainty on optimization was investigated by means of HTP for six different systems: the 70 MHz AMC-4 (AMC: Academic Medical Center) and AMC-8 system, a 130 MHz version of the AMC-8 system, a three-ring AMC-12 system operating at 130 MHz, the BSD SigmaEye applicator and a dipole applicator with three rings each containing six dipole pairs operated at 150 MHz. For five patients with cervix uteri carcinoma, a patient model was created based on a hyperthermia planning CT. Variation of tissue parameters resulted in 16 dielectric models for every patient. In addition, four thermal models were created to study the combined effect of perfusion and dielectric uncertainty. The impact of dielectric uncertainty on optimization is found to be clearly dependent on the number of channels and increased from 0.5 °C for four channels to 1.5 °C for the 18-channel system. As a result, the potential gain relative to the AMC-4 system for the 70 MHz AMC-8 system was found to be largely compromised, while for the remaining systems a robust improvement in T(90) was observed. The dipole applicator showed the best target heating for two out of five patients, while for three others heating efficacy was comparable to the 130 MHz AMC-12 system or the 130 MHz AMC-8 system (one patient). Considering the increase in complexity when the number of channels is increased from 12 to 18, the AMC-12 system is considered as a good compromise between heating efficacy and robustness while still being a manageable heating system in clinical practice.

Improved power steering with double and triple ring waveguide systems: the impact of the operating frequency.

INTRODUCTION: Regional hyperthermia systems with 3D power steering have been introduced to improve tumour temperatures. The 3D 70-MHz AMC-8 system has two rings of four waveguides. The aim of this study is to evaluate whether T(90) will improve by using a higher operating frequency and whether further improvement is possible by adding a third ring. METHODS: Optimised specific absorption rate (SAR) distributions were evaluated for a centrally located target in tissue-equivalent phantoms, and temperature optimisation was performed for five cervical carcinoma patients with constraints to normal tissue temperatures. The resulting T(90) and the thermal iso-effect dose (i.e. the number of equivalent min at 43°C) were evaluated and compared to the 2D 70-MHz AMC-4 system with a single ring of four waveguides. FDTD simulations were performed at 2.5 × 2.5 × 5 mm(3) resolution. The applied frequencies were 70, 100, 120, 130, 140 and 150 MHz. RESULTS: Optimised SAR distributions in phantoms showed an optimal SAR distribution at 140 MHz. For the patient simulations, an optimal increase in T(90) was observed at 130 MHz. For a two-ring system at 70 MHz the gain in T(90) was about 0.5°C compared to the AMC-4 system, averaged over the five patients. At 130 MHz the average gain in T(90) was ~1.5°C and ~2°C for a two and three-ring system, respectively. This implies an improvement of the thermal iso-effect dose with a factor ~12 and ~30, respectively. CONCLUSION: Simulations showed that a 130-MHz two-ring waveguide system yields significantly higher tumour temperatures compared to 70-MHz single-ring and double-ring waveguide systems. Temperatures were further improved with a 130-MHz triple-ring system.

3D versus 2D steering in patient anatomies: a comparison using hyperthermia treatment planning.

PURPOSE: In this study hyperthermia treatment planning is used to investigate whether the target temperature during hyperthermia treatment can be increased using the 3D AMC-8 instead of the 2D AMC-4 system (AMC: Academic Medical Center). METHODS AND MATERIALS: The heating ability of the AMC-4 and AMC-8 system was analysed for five patients with cervix uteri carcinoma. Dielectric and thermal models were generated, based on a hyperthermia planning computerised tomography (CT), at a resolution of 2.5 × 2.5 × 5.0 mm(3). Calculation of the electric fields with the finite-difference time-domain method was followed by SAR- and temperature-based optimisation. The ability to correct for axial shifts of the patient by phase/amplitude steering was investigated for both systems. Finally, it was investigated whether adjusting the ring-to-ring distance of the AMC-8 system can be used for further optimisation. RESULTS: An average increase in T(90) of ∼0.5°C (0.2°-0.8°C) was found for the AMC-8 system compared to the AMC-4 system. The gain in T(50) and T(10) was also 0.5°C on average. The additional power required to achieve this gain was 36% to 71% of the power required for the AMC-4 system. The AMC-8 system has the capability of correcting changes in axial position (-8 cm, +8 cm), contrary to the AMC-4 system. For both systems the axial position should be known within 1-2 cm. CONCLUSIONS: Hyperthermia treatment with the AMC-8 system can lead to a clinically relevant increase of the target temperature compared to treatment with the AMC-4 system. The AMC-8 system provides large freedom in the axial positioning of the patient.

Optimization in hyperthermia treatment planning: the impact of tissue perfusion uncertainty.

PURPOSE: Hyperthermia treatment planning (HTP) potentially provides a valuable tool for monitoring and optimization of treatment. However, one of the major problems in HTP is that different sources of uncertainty degrade its reliability. Perfusion uncertainty is one of the largest uncertainties and hence there is an ongoing debate whether optimization should be limited to power-based strategies. In this study a systematic analysis is carried out addressing this question. METHODS: The influence of perfusion uncertainty on optimization was analyzed for five patients with cervix uteri carcinoma heated with the AMC-8 70 MHz phased-array waveguide system. The effect of variations (up to +/- 50%) in both the muscle and tumor perfusion level was investigated. For every patient, reference solutions were calculated using constrained temperature-based optimization for 25 different and known perfusion distributions. Reference solutions were compared to those found by temperature-based optimization using standard perfusion values and four SAR-based optimization methods. The effect of heterogeneity was investigated by creating 5 x 100 perfusion distributions for different levels of local variation (+/- 25% and +/- 50%) and scale (1 and 2 cm). Here the performance of the temperature-based optimization method was compared to a SAR-based method that showed good performance in the previous analysis. RESULTS: Solutions found with temperature-based optimization using a deviating perfusion distribution during optimization were found within 1.0 degrees C from the true optimum. For the SAR-based methods, deviations up to 2.9 degrees C were found. The spread found in these deviations was comparable, typically 0.5-1.0 degrees C. When applying intramuscle variation to the perfusion, temperature-based optimization proved to be the best strategy in 95% of the evaluated cases applying +/- 50% local variation. CONCLUSIONS: Temperature-based optimization proves to be superior to SAR-based optimization both under variation of perfusion level as well as under the application of intratissue variation. The spread in achieved temperatures is comparable. These results are valid under the assumption of constant perfusion at hyperthermic levels. Although similar results are expected from models including thermoregulation, additional analysis is required to confirm this. In view of uncertainty in tissue perfusion and other modeling uncertainties, the authors propose feedback guided temperature-based optimization as the best candidate to improve thermal dose delivery during hyperthermia treatment.