H. P. Kok

Improving locoregional hyperthermia delivery using the 3-D controlled AMC-8 phased array hyperthermia system: A preclinical study

Background: The aim of this study is preclinical evaluation of our newly developed regional hyperthermia system providing 3-D SAR control: the AMC-8 phased array consisting of two rings, each with four 70 MHz waveguides. It was designed to achieve higher tumour temperatures and improve the clinical effectiveness of locoregional hyperthermia. Methods: The performance of the AMC-8 system was evaluated with simulations and measurements aiming at heating a centrally located target region in rectangular (30 × 30 × 110 cm) and elliptical (36 × 24 × 80 cm) homogeneous tissue equivalent phantoms. Three properties were evaluated and compared to its predecessor, the 2-D AMC-4 single ring four waveguide array: (1) spatial control and (2) size of the SAR focus, (3) the ratio between maximum SAR outside the target region and SAR in the focus. Distance and phase difference between the two rings were varied. Results: (1) Phase steering provides 3-D SAR control for the AMC-8 system. (2) The SAR focus is more elongated compared to the AMC-4 system, yielding a lower SAR level in the focus when using the same total power. This is counter-balanced by (3) a superficial SAR deposition which is half of that in the AMC-4 system, yielding a more favourable ratio between normal tissue and target SAR and allowing higher total power and up to 30% more SAR in the focus for 3 cm ring distance. Conclusion: The AMC-8 system is capable of 3-D SAR control and its SAR distribution is more favourable than for the 2-D AMC-4 system. This result promises improvement in clinical tumour temperatures.

High-resolution temperature-based optimization for hyperthermia treatment planning

In regional hyperthermia, optimization techniques are valuable in order to obtain amplitude/phase settings for the applicators to achieve maximal tumour heating without toxicity to normal tissue. We implemented a temperature-based optimization technique and maximized tumour temperature with constraints on normal tissue temperature to prevent hot spots. E-field distributions are the primary input for the optimization method. Due to computer limitations we are restricted to a resolution of 1 x 1 x 1 cm3 for E-field calculations, too low for reliable treatment planning. A major problem is the fact that hot spots at low-resolution (LR) do not always correspond to hot spots at high-resolution (HR), and vice versa. Thus, HR temperature-based optimization is necessary for adequate treatment planning and satisfactory results cannot be obtained with LR strategies. To obtain HR power density (PD) distributions from LR E-field calculations, a quasi-static zooming technique has been developed earlier at the UMC Utrecht. However, quasi-static zooming does not preserve phase information and therefore it does not provide the HR E-field information required for direct HR optimization. We combined quasi-static zooming with the optimization method to obtain a millimetre resolution temperature-based optimization strategy. First we performed a LR (1 cm) optimization and used the obtained settings to calculate the HR (2 mm) PD and corresponding HR temperature distribution. Next, we performed a HR optimization using an estimation of the new HR temperature distribution based on previous calculations. This estimation is based on the assumption that the HR and LR temperature distributions, though strongly different, respond in a similar way to amplitude/phase steering. To verify the newly obtained settings, we calculate the corresponding HR temperature distribution. This method was applied to several clinical situations and found to work very well. Deviations of this estimation method for the AMC-4 system were typically smaller than 0.2 degrees C in the volume of interest, which is accurate enough for treatment planning purposes.

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.

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.

Prospective treatment planning to improve locoregional hyperthermia for oesophageal cancer

Background: In the Academic Medical Center (AMC) Amsterdam, locoregional hyperthermia for oesophageal tumours is applied using the 70 MHz AMC-4 phased array system. Due to the occurrence of treatment-limiting hot spots in normal tissue and systemic stress at high power, the thermal dose achieved in the tumour can be sub-optimal. The large number of degrees of freedom of the heating device, i.e. the amplitudes and phases of the antennae, makes it difficult to avoid treatment-limiting hot spots by intuitive amplitude/phase steering. Aim: Prospective hyperthermia treatment planning combined with high resolution temperature-based optimization was applied to improve hyperthermia treatment of patients with oesophageal cancer. Methods: All hyperthermia treatments were performed with ‘standard’ clinical settings. Temperatures were measured systemically, at the location of the tumour and near the spinal cord, which is an organ at risk. For 16 patients numerically optimized settings were obtained from treatment planning with temperature-based optimization. Steady state tumour temperatures were maximized, subject to constraints to normal tissue temperatures. At the start of 48 hyperthermia treatments in these 16 patients temperature rise (ΔT) measurements were performed by applying a short power pulse with the numerically optimized amplitude/phase settings, with the clinical settings and with mixed settings, i.e. numerically optimized amplitudes combined with clinical phases. The heating efficiency of the three settings was determined by the measured ΔT values and the ΔT-ratio between the ΔT in the tumour (ΔToes) and near the spinal cord (ΔTcord). For a single patient the steady state temperature distribution was computed retrospectively for all three settings, since the temperature distributions may be quite different. To illustrate that the choice of the optimization strategy is decisive for the obtained settings, a numerical optimization on ΔT-ratio was performed for this patient and the steady state temperature distribution for the obtained settings was computed. Results: A higher ΔToes was measured with the mixed settings compared to the calculated and clinical settings; ΔTcord was higher with the mixed settings compared to the clinical settings. The ΔT-ratio was ∼1.5 for all three settings. These results indicate that the most effective tumour heating can be achieved with the mixed settings. ΔT is proportional to the Specific Absorption Rate (SAR) and a higher SAR results in a higher steady state temperature, which implies that mixed settings are likely to provide the most effective heating at steady state as well. The steady state temperature distributions for the clinical and mixed settings, computed for the single patient, showed some locations where temperatures exceeded the normal tissue constraints used in the optimization. This demonstrates that the numerical optimization did not prescribe the mixed settings, because it had to comply with the constraints set to the normal tissue temperatures. However, the predicted hot spots are not necessarily clinically relevant. Numerical optimization on ΔT-ratio for this patient yielded a very high ΔT-ratio (∼380), albeit at the cost of excessive heating of normal tissue and lower steady state tumour temperatures compared to the conventional optimization. Conclusion: Treatment planning can be valuable to improve hyperthermia treatments. A thorough discussion on clinically relevant objectives and constraints is essential.

Body Conformal Antennas for Superficial Hyperthermia: The Impact of Bending Contact Flexible Microstrip Applicators on Their Electromagnetic Behavior

Hyperthermia is a powerful radiosensitizer for treatment of superficial tumors. This requires body conformal antennas with a power distribution as homogeneous as possible over the skin area. The contact flexible microstrip applicators (CFMA) operating at 434 MHz exist in several sizes, including the large size 3H and 5H. This paper investigates the behavior of the electromagnetic fields for the 3H and 5H CFMA in both flat and curved configurations, and the impact on performance parameters like the penetration depth (PD) and the effective heating depth (EHD). The underlying theory behind the electromagnetic behavior in curved situations is presented as well as numerical simulations of both flat and curved configurations. The results are compared to measurements of the electromagnetic field distributions in a cylindrical patient model. Due to their large size multimode solutions may exist, and our results confirm their existence. These multimode solutions affect both the power distribution and PD/EHD, with a dependence on applicator curvature. Therefore, the performance parameters like PD and EHD need to be carefully assessed when bending large size CFMA applicators to conform to the patient body. This conclusion also holds for other types of large size surface current applicators.

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 mm3. 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 T90 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 T50 and T10 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.

On verification of hyperthermia treatment planning for cervical carcinoma patients.

Purpose: The aim of this study was to verify hyperthermia treatment planning calculations by means of measurements performed during hyperthermia treatments. The calculated specific absorption rate (SARcalc) was compared with clinically measured SAR values, during 11 treatments in seven cervical carcinoma patients. Methods: Hyperthermia treatments were performed using the 70 MHz AMC-4 waveguide system. Temperatures were measured using multisensor thermocouple probes. One invasive thermometry catheter in the cervical tumour and two non-invasive catheters in the vagina were used. For optimal tissue contact and fixation of the catheters, a gynaecological tampon was inserted, moisturized with distilled water (4 treatments), or saline (6 treatments) for better thermal contact. During one treatment no tampon was used. At the start of treatment the temperature rise (ΔTmeas) after a short power pulse was measured, which is proportional to SARmeas. The SARcalc along the catheter tracks was extracted from the calculated SAR distribution and compared with the ΔTmeas-profiles. Results: The correlation between ΔTmeas and SARcalc was on average R = 0.56 ± 0.28, but appeared highly dependent on the wetness of the tampon (preferably with saline) and the tissue contact of the catheters. Correlations were strong (R ∼ 0.85–0.93) when thermal contact was good, but much weaker (R ∼ 0.14–0.48) for cases with poor thermal contact. Conclusion: Good correlations between measurements and calculations were found when tissue contact of the catheters was good. The main difficulties for accurate verification were of clinical nature, arising from improper use of the gynaecological tampon. Poor thermal contact between thermocouples and tissue caused measurement artefacts that were difficult to correlate with calculations.

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 T90 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 T90 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 mm3 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 T90 was observed at 130 MHz. For a two-ring system at 70 MHz the gain in T90 was about 0.5°C compared to the AMC-4 system, averaged over the five patients. At 130 MHz the average gain in T90 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.

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.