P. Van Haaren

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.

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.

Preoperative chemoradiation combined with regional hyperthermia for patients with resectable esophageal cancer

Purpose: To analyse the treatment results of neo-adjuvant chemoradiation combined with regional hyperthermia in patients with resectable esophageal cancer. Patients and methods: Between August 2003 and December 2004, 28 patients entered a phase II study combining chemoradiation over a 4.5-week period with five sessions of regional hyperthermia. Chemotherapy consisted of carboplatin (AUC = 2) and paclitaxel (50 mg/m2) and radiotherapy of 41.4 Gy in 1.8 Gy daily fractions. Locoregional hyperthermia was applied using the AMC phased array of four 70 MHz antennas, aiming at a stable tumor temperature of 41°C for one hour. Carboplatin was infused during the hyperthermia session. Esophageal resection was planned at 6–8 weeks after the end of radiotherapy. The majority of the patients had a T3 tumor (86%) and were cN+ (64%). Median follow-up for survivors was 37 months (range 31–46). Results: Twenty-five patients (89%) completed the planned neo-adjuvant treatment and acute toxicity was generally mild. Twenty-six patients were operated on. A pathologically CR, PRmic, PR and SD were seen in 19%, 27%, 31% and 23% respectively. All patients had a R0 resection. In-field locoregional control during follow up for the operated patients was 100%. Quality of life was good for patients without disease progression. Survival rates at one, two and three years were 79%, 57% and 54% respectively. Conclusion: Neo-adjuvant chemoradiation combined with regional hyperthermia followed by esophageal resection for patients with esophageal cancer resulted in good locoregional control and overall survival.

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.

Relation between body size and temperatures during locoregional hyperthermia of oesophageal cancer patients

Purpose. To analyse the relation between patients’ body size and temperatures during locoregional hyperthermia for oesophageal cancer. Methods. Patients were treated with neo-adjuvant chemoradiotherapy plus hyperthermia, given with the AMC-4 waveguide system. Temperatures were measured at tumour location in the oesophageal lumen using multisensor thermocouple probes. Systemic temperature rise (ΔTsyst) was monitored rectally. Steady-state tumour temperatures were expressed in terms of T90, T50 and T10, averaged over the five hyperthermia sessions, and correlated with patients’ body mass, dorsoventral and lateral diameter and fat layer thickness, measured at tumour level using a CT scan made in treatment position. Fat percentage (Fat%) was estimated using diameters and fat layer thickness. Effective tumour perfusion (Wb) was estimated from the temperature decay during the cool-down period. Results. Temperatures were inversely related to body mass, diameters, fat layer thickness, and fat percentage. The strongest univariate correlations were found with lateral fat layer thickness, lateral diameter, and body mass. An increase in lateral diameter (28→42 cm), or in lateral fat layer thickness (0→40 mm) or in body mass (50→120 kg) all yielded a ∼1.5°C decrease in tumour temperature rise. Multivariate correlation analysis proved that the combination of Fat%, ΔTsyst and Wb was most predictive for the achieved tumour temperatures, accounting for 81 ± 12% of the variance in temperatures. Conclusions. Intra-oesophageal temperatures during locoregional hyperthermia are inversely related to patients’ body size parameters, of which fat percentage is the most significant prognostic factor. These findings could be used to define inclusion criteria of new studies on intrathoracic hyperthermia.

A comprehensive evaluation of treatment accuracy, including end-to-end tests and clinical data, applied to intracranial stereotactic radiotherapy

BACKGROUND AND PURPOSE A methodology is presented to quantify the uncertainty associated with linear accelerator-based frameless intracranial stereotactic radiotherapy (SRT) combining end-to-end phantom tests and clinical data. METHODS AND MATERIALS The following steps of the SRT chain were analysed: planning computed tomography (CT) and magnetic resonance (MR) scans registration, target volume delineation, CT and cone beam CT (CBCT) registration and intrafraction-patient displacement. The overall accuracy was established with an end-to-end test. The measured uncertainties were combined, deriving the total systematic (ΣT) and random (σT) error components, to estimate the GTV-PTV margin. RESULTS The uncertainty in the MR-CT registration was on average 0.40mm (averaged over AP, CC and LR directions). Rotational variations were smaller than 0.5° in all directions. Interobser variation in GTV delineation was on average 0.29mm. The uncertainty in the CBCT-CT registration was on average 0.15mm. Again, rotational variations were smaller than 0.5° in all directions. The systematic and random intrafraction displacement errors were on average 0.55mm and 0.45mm, respectively. The systematic and random positional errors from the end-to-end test were on average 0.49mm and 0.53mm, respectively. Combining these uncertainties resulted in an average ΣT=0.9mm and σT=0.7mm and an average GTV-PTV margin of 2.8mm. CONCLUSION This comprehensive methodology including end-to-end tests enabled a GTV-PTV margin calculation considering all sources of uncertainties. This generic method can also be used for other treatment sites.

Radiotherapy combined with hyperthermia for primary malignant melanomas of the esophagus.

Primary malignant melanoma of the esophagus (PMME) forms about 0.1% of all primary esophageal cancers. Treatment options are very limited for patients unfit for surgery. This is the first report describing the results of external radiotherapy combined with regional hyperthermia for two inoperable PMME patients. Two patients with a T2-3N0M0 PMME were considered unfit for surgery based on age and general condition. External radiotherapy of a total dose of 35 Gy was given in a scheme of seven times 5 Gy, two times per week, and once weekly combined with external and intraluminal hyperthermia (aim 43°C). Toxicity was mild and both patients completed treatment according to protocol. Adequate temperatures at the intraluminal border of the tumor were achieved. In both patients, a complete remission was achieved with complete relief of obstructive symptoms and without signs of locoregional tumor progression until the end of follow-up at 11 and 15 months. External radiation combined with regional hyperthermia could be a good alternative to resection in patients unfit for surgery with a malignant melanoma of the esophagus.

Theoretical comparison of intraluminal heating techniques

Introduction: This study compared simulated temperature distributions of intraluminal heating devices, concerning penetration and homogeneity. A hot water balloon, a 434-MHz monopole and a 915-MHz dipole antenna, both with incorporated cooling, and a 27-MHz applicator were investigated. Methods: The hot water balloon had an inlet temperature of 45°C and a flow rate of 7.85 ml s−1. The cooling water and air had a temperature of 41°C and 37°C and a flow rate of 5.89 ml s−1 and 1.8 l s−1, respectively. A 27-MHz applicator consisting of one or two electrode(s) was modelled to demonstrate axial steering for inhomogeneous tissue properties. Calculated power distributions were scaled to a total power of 10 W in tissue before the corresponding temperature distributions were calculated. Results: The hot water balloon and the 27-MHz device showed a thermal penetration depth of ∼4 and ∼10 mm, respectively. The penetration depths of the 434- and 915-MHz applicators were comparable: ∼10 and ∼16 mm with water and air cooling, respectively. With the 27-MHz applicator, spatial steering was applied to minimize temperature gradients along the applicator. The 434- and 915-MHz antennas have no steering possibilities. The temperature distribution of the hot water balloon is not affected by inhomogeneous dielectric properties, only slightly by inhomogeneous perfusion. Conclusion: A hot water balloon is useful for heating tumours with a limited infiltration in tissue, while a 27-MHz device has the best potential to realize a homogeneous temperature distribution in larger tumours.

Reliability of temperature and SAR measurements at oesophageal tumour locations

Introduction: For treatment of oesophageal cancer, neo-adjuvant locoregional hyperthermia (HT) has been applied in combination with chemotherapy (ChT) ± radiotherapy (RT) at the institute. Until now, 26 patients were treated within a completed phase I study combining HT with ChT and 29 patients within an ongoing phase II study combining HT with ChT + RT. Methods: HT was given with the 70 MHz AMC-4 waveguide system. Initially, oesophageal temperatures were measured using multi-sensor thermocouple probes (TCs) inside a nasogastric tube (NT), but the question arose whether these measurements were reliable enough to quantify the achieved tumour temperatures accurately. Presently, TCs are mounted on the outside of an inflatable balloon catheter (BC) for better intra-luminal fixation and better contact with the tumour. During 14 treatment sessions in four patients TCs inside a NT and mounted on a BC were used simultaneously. Data from these 14 treatment sessions were used to compare temperature and Specific Absorption Rate (SAR) measurements (‘ΔT-measurements’) using NTs or BCs. To determine the predictive value of the local SAR for the tumour temperatures achieved during treatment, the relation between the initial ΔT and steady state temperature (SST) was evaluated. Results: There was a strong correlation between the temperature measured in the NT (Ttube) and the temperature measured with a BC (Tballoon): R = 0.88 ± 0.13. However, Ttube was on average ∼1°C higher than Tballoon and there was a large variation between the different treatments in the relation between both measurements, rendering Ttube a probably unreliable measure for tumour temperatures. The correlation between the ΔT measured in the NT (ΔTtube) and with a BC (ΔTballoon) was rather weak: R = 0.46 ± 0.25. The correlation between the initial ΔT and the SST was much stronger for the BC measurements, R = 0.78 ± 0.19, than for the NT measurements, R = 0.61 ± 0.23. Thus, ΔTballoon has a higher predictive value for the achieved tumour temperatures than ΔTtube. Both ΔT and SST were generally higher for the NT measurements than for the BC measurements, suggesting an over-estimation of tumour temperatures. Averaged over all treatments in the phase I trial using a NT (20 treatments) or a BC (45 treatments), T90 was significantly higher when measured with a NT. Conclusion: Oesophageal temperature and SAR (ΔT) measurements inside a NT are less reliable than BC measurements. These artefacts are due to bad thermal contact with the tumour tissue and are, therefore, not specific for thermocouple thermometry. For reliable temperature or SAR measurements inside lumina or cavities good thermal contact must be assured, e.g. by using a balloon catheter.