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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 x 30 x 110 cm) and elliptical (36 x 24 x 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.

The optimal feed parameters of the generators for a complex-phased hyperthermia array system consisting of 4, 8 or even more applicators cannot be found using only the expertise of the treatment staff or using the limited amount of field and temperature data obtained during treatment. A number of strategies have been proposed to help us with the task to optimise the hyperthermia treatment, including several strategies specifically addressing the occurrence of hot spots. Each of the latter strategies strongly relies on the specification of the potential hot spots. This specification is either based on anatomy or the selection of an arbitrary number of potential hot spots. Therefore it is not guaranteed that all potential hot spots are included. This paper introduces a procedure for the delineation and visualisation of potential (SAR) hot spots. The potential hot spots are delineated by selecting those points for which the maximal SAR exceeds a specific SAR selection level. This SAR selection level is defined relative to the highest achievable SAR in the target volume for a certain fixed heating power. A larger number of potential hot spots and hot spots of larger size are delineated if the selection level is decreased. Although the procedure still includes an arbitrary selection criterion, i.e. the selection level, the selection is solely based on calculated EM-field data. As a result all potential hot spots can be delineated a priori. Three different objective functions are applied to maximise the SAR in the target. The first only maximises the SAR in the target volume for a given system power output. The other two intrinsically set a constraint on the set of potential hot spots as a whole. Additionally the SAR in each delineated potential hot spot separately can be constrained. In two patient cases the SAR in potential hot spots can be kept below the selection value applied for delineation of the potential hot spots. If assessed in terms of constraining the SAR value below the selection level while maximising target heating efficiency the combination of an objective function only maximising the SAR in the target with a separate constraint on each potential hot spots appears to be the most efficient.

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 ('DeltaT-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 DeltaT 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 approximately 1 degrees 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 DeltaT measured in the NT (DeltaTtube) and with a BC (DeltaTballoon) was rather weak: R = 0.46 +/- 0.25. The correlation between the initial DeltaT 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, DeltaTballoon has a higher predictive value for the achieved tumour temperatures than DeltaTtube. Both DeltaT 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 (DeltaT) 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.

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.

During intraluminal or intracavitary hyperthermia treatments, limited non-invasive temperature information is available, which may result in sub-optimal treatment control. This article describes a method for estimating temperature maximums and their corresponding locations in tissue heated by a cylindrical applicator with an incorporated cooling system, assuming a hollow cylinder of homogeneous tissue. The main purpose of this study is intraluminal heating of tumours at the oesophagus, but the principle described is generally applicable for cylindrical applicators. When assuming no perfusion and only radial heat flow in the heated tissue, an analytical expression for the temperature profile can be derived such that the complete profile can be reconstructed from the inner wall temperature only. For situations with perfusion, finite difference simulations have been performed and the resulting simulated inner wall temperature was put into the analytical expression to obtain an estimation for the maximum temperature and the corresponding location. This way, an estimation method was developed which does not require a priori knowledge of the perfusion rate or invasive thermometry. For volumetric perfusion rates in the clinically relevant range of 0-10 kg m-3 s-1, the deviations between simulated and estimated temperature maximums were less than 10% and the difference in location was typically a few tenths of a millimetre. These deviations are small enough for treatment control purposes.

Objective: Hyperthermia enhances carboplatin cytotoxicity preclinically, and clinical studies have shown radiant heat Whole Body Hyperthermia (WBH) to be safe. In this study, the efficacy and toxicity of the combination of 41.8 degrees C WBH and carboplatin in recurrent and/or metastatic cervical cancer were explored., Methods: Recurrent and/or metastatic cervical cancer patients were treated with 41.8 degrees C WBH and concurrent carboplatin, cycled every 28 days (max. 6 cycles)., Results: Twenty-one of 25 participants were evaluable for response: one complete remission, six partial responses, stable disease in nine patients and progression in five, leading to a response rate of 33%. Three of four evaluable chemotherapy pre-treated patients progressed, while this was seen in only 2 of 17 chemotherapy-naive patients. The median survival is 7.8 months (range 1.3 to 43+) and no patients were lost to follow up. Grades 3/4 toxicities were common: leukopenia in 35%, thrombopenia in 61% and anemia in 22% of all treatments. Excessive, partly reversible renal toxicity was seen in two patients (grades 3 and 4)., Conclusion: The efficacy of WBH and carboplatin in recurrent and/or metastatic cervical cancer seems comparable to that of other palliative chemotherapy regimens in this disease. The considerable toxicity, though largely manageable, includes unexpected and severe unacceptable renal toxicity. This regimen seems less suitable for palliative care.

This phase I-II study investigated the feasibility of external deep loco-regional hyperthermia in localized primarily operable carcinoma of the thoracic oesophagus and gastro-oesophageal junction. Toxicity when combining neo-adjuvant hyperthermia with concurrent chemotherapy (CDDP and etoposide) was evaluated. Hyperthermia was given with a four antenna array, operating at 70 MHz arranged around the thorax. Temperatures were monitored rectally, intra-oesophageal at tumour level and intramuscular near the spine. In four steps, a thermal dose escalation was performed from 15-60 min of heating to 41 degrees C with two patients in each step. The combined treatment courses were repeated every 3 weeks for a maximum of four courses. From January 1999-February 2002, 31 patients were included. Pre-treatment tumour stage mainly consisted of T3N1 (stage III) tumours, with a mean length of 6 cm. The maximum tumour temperature failed to reach at least 41 degrees C in five patients during the test session of hyperthermia alone. Combined hyperthermia and chemotherapy was given 55 times in 26 patients. The amplitude was set at a ratio between top:bottom:left:right = 1:3:3:3, with a power range of 800-1000 W. Thermal data showed that is was technically feasible to heat the oesophagus; the median results were T(90) = 39.3 degrees C, T(50) = 40 degrees C, T(10) = 40.7 degrees C and a median T(max) = 41.9 degrees C. In more distally located tumours higher temperatures were reached. In one patient, a transient grade 2 sensory neuropathy was seen. Further toxicity was mainly of haematological origin. Blisters or fat necrosis were not observed. Twenty-two patients underwent oesophageal-cardia resection with gastric tube reconstruction. There was no report of complications in the post-operative phase, which could be contributed to either the prior chemotherapy or the hyperthermia.

Background: Based on earlier clinical and preclinical studies, we conducted a phase II trial in metastatic sarcoma patients of the combination of 41.8 degrees C (x60 min) radiant heat (Aquatherm) whole-body hyperthermia (WBH) with 'ICE' chemotherapy. The ICE regimen consists of ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (100 mg/m(2)), concurrent with WBH, with etoposide also on days 2 and 3 post-WBH., Methods: Therapy was delivered every 4 weeks for a maximum of 4 cycles. All patients received filgrastim or lenograstim., Results: Of 108 patients enrolled as of September 2001, 95 are evaluable for response. Of the evaluable patients (mean ECOG performance status approximately 1; mean age 42.3; 58% male) 33 had no prior therapy for metastatic disease, and 62 were pretreated (mean: 1.5 prior regimens). The overall response rate was 28.4% (4 complete remissions and 23 partial remissions) with stable disease (SD) in 31 patients. For no prior therapy, the response rate was 36%; in pretreated patients it was 24%. The median overall survival by Kaplan-Meier estimates was 393 days (95% CI 327, 496); the median time to treatment failure was 123 days (95% CI 77, 164). The major toxicity (287 cycles) was grade 3 or 4 neutropenia and thrombocytopenia seen in 79.7 and 60.6% of treatments respectively; there were 7 episodes of infection (grade 3/4) with 2 treatment-related deaths, bot involving disease progression and ureteral obstruction., Conclusion: These results are consistent with continued clinical investigation of this combined modality approach., (Copyright 2003 S. Karger AG, Basel)

In hyperthermia treatments performed with a radio-frequency phased array, the main issue to apply the excitation amplitudes and phases of the applicators for which tumour heating is optimal, i.e. the maximal therapeutic gain without unwanted side effects. Due to the complex interaction of the radiated EM-field and the patient's tissues, it is very difficult to find these optimal excitation (amplitude and phase) parameters by intuition. Calculation of the EM-field distribution within the patient can aid in finding the optimal excitation setting. However, this remains a difficult task because of the degrees of freedom available (2n - 1, with n the number of applicators in the array) and because a large temperature elevation may occur at healthy tissue sites resulting in unwanted side effects, e.g. pain or healthy tissue damage. Therefore, determining the excitation amplitudes and phases yielding optimal tumour heating can be done effectively only by application of a computerized optimization procedure. Optimization of the temperature distribution in the patient requires detailed knowledge of the thermal tissue parameters. Techniques for determining these properties are not commonly available and the use of averaged values for parameters like the tissue perfusion is expected to introduce large errors for individual patient treatment planning. As a consequence, the SAR distribution, being proportional to the temperature increase at treatment start, is more often selected for optimization. The 'optimized' excitation amplitudes and phases are found by maximization of a certain SAR ratio. Several propositions for this SAR ratio have been reported in the literature, e.g. the ratio of the SAR at the tumour site and the SAR at sites where unwanted side effects may occur. However, the definition of these ratios does not constrain the SAR value at these tissue locations to a safe value. In this paper, a tool for the optimization of the SAR distribution including the specification of constraints is presented. The tool focuses on the definition of the average SAR as a function of the excitation amplitudes and phases in a volume of arbitrary size (e.g. the tumour volume or the whole patient volume). These functions can be applied in either customized or commercially available optimization routines and they enable the definition of constraints for the average SAR in a certain volume. The described tool is illustrated for a patient case, showing the flexibility and easy application of the tool.

The aim of this study was to determine whether the addition of whole body hyperthermia (WBH) to carboplatin (CBDCA) can induce responses in patients with platinum-resistant ovarian cancer. 16 pretreated patients with platinum-resistant ovarian cancer were entered on a Systemic Hyperthermia Oncological Working Group (SHOWG) study; (14 patients were eligible with 14 evaluable for toxicity and 12 for response). The patients were treated with WBH (Aquatherm) 41.8 degrees C x 60 min in combination with carboplatin (CBDCA) (area under the curve (AUC) of 8) every 4 weeks. Disease status was evaluated every two cycles. Patients were treated for a maximum of six cycles. One patient had a complete response (CR) and 4 had a partial response (PR). 4 patients had stable disease (SD). 3 patients had progressive disease (PD). 2 patients were unevaluable: 1 had a bowel obstruction shortly after her first treatment; the second patient achieved a CR, but only had one treatment secondary to an idiosyncratic reaction to sedative drugs. 2 patients entered on study were ineligible, as they did not meet criteria for platinum resistance; 1 entered a CR and 1 had SD. Dose-limiting toxicity, which required CBDCA dose reductions, was grade 4 thrombocytopenia. Other toxicities included neutropenia (grade 3/4), and nausea and/or vomiting. Consistent with preclinical modelling, these results suggests that 41.8 degrees C WBH can overcome platinum resistance in ovarian cancer. These observations suggest further investigation of the therapeutic potential of WBH in a group of patients who historically fail to respond to salvage therapies is warranted.

The accuracy of a hyperthermia treatment simulation determines its role in prospective treatment planning and dosimetry for the individual patient. Of importance are (1) the accuracy of the numerical simulation method, and (2) the numerical description of the hyperthermia treatment system. The accuracy of the numerical method is generally determined by analysis of a problem that is analytically solvable. The validity of the description of the hyperthermia system is to be investigated by comparison of the simulated and measured EM-field amplitude and phase of the clinical operational hyperthermia system. In this paper, the numerical description of the AMC-4 waveguide phased array for which treatment planning is performed by the Weak Form of the Conjugate Gradient FFT method is investigated. The accuracy of the description is analysed for four set-ups, varying the bolus size and the number of waveguides attached to a phantom. The comparison of experimental and numerical data has demonstrated the ability of the Weak Formulation of the Conjugate Gradient FFT method to predict the EM-field of the AMC-4 waveguide array hyperthermia system, including effects due to bolus size variations. However, based on the comparison of the measured EM-field distributions and those obtained from simulations, the accuracy of the planning system is found to be insufficient for quantitative SAR dosimetry for individual patients. Qualitative SAR dosimetry can be applied in cases where the accuracy is of minor importance, e.g. for the retrospective analysis of problematic hyperthermia treatments. Prospective applications of the treatment planning system include the (qualitative) determination/simulation of a set of starting points giving a 'close to optimal' amplitude and phase setting, the prediction of possible problem areas and the analysis of the performance of new/improved hyperthermia devices.

Background: Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy., Methods: The study was a prospective, randomised, multicentre trial. 358 patients were enrolled from 1990 to 1996, in cancer centres in the Netherlands, who had bladder cancer stages T2, T3, or T4, NO, MO, cervical cancer stages IIB, IIIB, or IV, or rectal cancer stage M0-1 were assessed. Patients were randomly assigned radiotherapy (median total dose 65 Gy) alone (n=176) or radiotherapy plus hyperthermia (n=182). Our primary endpoints were complete response and duration of local control. We did the analysis by intention to treat., Findings: Complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia (p<0.001). The duration of local control was significantly longer with radiotherapy plus hyperthermia than with radiotherapy alone (p=0.04). Treatment effect did not differ significantly by tumour site, but the addition of hyperthermia seemed to be most important for cervical cancer, for which the complete-response rate with radiotherapy plus hyperthermia was 83% compared with 57% after radiotherapy alone (p=0.003). 3-year overall survival was 27% in the radiotherapy group and 51% in the radiotherapy plus hyperthermia group. For bladder cancer, an initial difference in local control disappeared during follow-up., Interpretation: Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made.

The limited aperture size through which the em-field of the applicator is emanated and the constraining of this em-field near the bolus' edge is related to the appearance of superficial 'hot spot' phenomena in radiative hyperthermia. Regarding systems based on the concept of the annular phased array two questions arise: (1) what is the relative strength of the radial component present in the incident field of the radiators, and (2) in what way are fringing fields related to the bolus size? To address both of the above questions, the spatial distribution of the em-field emanated through the aperture of an applicator of the Amsterdam four waveguide-array system has been investigated for a long bolus and a short bolus. The em vector field emanated by the applicator has been characterized in two perpendicular planes, i.e. the aperture midplane and the sagittal midplane. It should be noted that this distribution depends on the propagation conditions throughout the coupling bolus, the phantom and other volumes attached, such as other applicators. Therefore two sets of propagation conditions have been measured: (1) the minimum number of parameters determining the propagation of the em-field namely one single waveguide, one bolus and a homogeneous phantom, and (2) the propagation conditions as for the clinical setting. It is stressed that the study concerns one specific radiative hyperthermia system, namely the AMC four-waveguide array, but that, based on the similarities discussed above, results may be extrapolated towards other radiative hyperthermia systems. According to the current study, bolus prolongation might lead to a clear clinical improvement, which is due to a decrease of the fringing field amplitude compared to the field amplitude in the centre of the aperture midplane. Bolus prolongation will lead to an extended heating area, the field lines being more aligned to the patient's main axis.

The Technical Committee and the Clinical Committee of the ESHO evaluated the experience of the institutes which are active in clinical regional hyperthermia using radiative equipment. Based on this evaluation, QA guidelines have been formulated. The focus of these guidelines lies on what must be done not on how it should be done. Subjects covered are: treatment planning, treatment, treatment documentation, requirements and characterization of equipment, safety aspects, hyperthermia staff requirements and instrumentation for quality assurance.

The results from simulations with a new three-dimensional treatment planning system for interstitial hyperthermia with ferromagnetic seeds are presented in this study. The thermal model incorporates discrete vessel structures as well as a heat sink and enhanced thermal conductivity. Both the discrete vessels and the ferroseeds are described parametrically in separate calculation spaces. This parametric description has the advantage of an arbitrary orientation of the structures within the tissue grid, easy manipulation of the structures and independence from the resolution of the tissue voxels (tissue calculation space). The power absorption of the self-regulating seeds is according to empirical data. The thermal effects of an unlimited number of thin layers surrounding the seed (coatings, catheters) can be modelled. The initial calculations have been performed for an array of 12 identical ferromagnetic seeds in a tissue volume with a computer generated artificial vessel network spanning four vessel generations in both the arterial and venous tree. The heterogeneously distributed large isolated vessels impair the temperature distribution significantly, indicating the limited accuracy of continuum models. Simulations with different types of ferromagnetic seeds have confirmed that the efforts of previous studies to optimize the self-regulating temperature control and the implantation techniques of the ferroseeds will improve the homogeneity of the temperature distribution in the target volume. Multifilament seeds implanted in brachytherapy needles and tubular seeds appear to be the most favourable configurations. The division of long seeds into shorter segments with the appropriate Curie temperature will further improve the homogeneity of the temperature distribution without increasing the average temperature in the volume of interest. Given the proper thermal tissue data, the model presented in this study will prove to be a useful tool in making choices for the implant geometry, seed spacing and Curie temperature.

Purpose: The objective of this study was to determine whether the thermal dose delivered during hyperthermia treatments and other thermal factors correlate with outcome after combined radiation and hyperthermia of breast carcinoma recurrences. Data were from the combined hyperthermia and radiation treatment arms of four Phase III trials, which when pooled together, demonstrated a positive effect of hyperthermia., Methods and Materials: Four Phase III trials addressing the question of whether hyperthermia could improve the local response of superficial recurrent breast cancer to radiation therapy were combined into a single analysis. Thermal dosimetry data were collected from 120 of the 148 breast cancer recurrence patients who received hyperthermia. The data were analyzed for correlations between thermal parameters as well as important clinical parameters and outcome (complete response rate, local disease free survival, time to local failure, and overall survival)., Results: Five thermal parameters were tested, all associated with the low regions of the measured temperature distributions. Max(TDmin) and Sum(TDmin) were associated with complete response where TDmin is the minimum thermal dose measured by any of the tumor temperature sensors during a treatment: Max(TDmin) is the maximum of TDmin over a series of treatments. Using a categorical relationship with a cutoff of 10 min for Sum(TDmin), the complete response rate was 77% for Sum(TDmin) > 10 min and 43% for Sum(TDmin) < or = 10 min (p = 0.022, adjusted for study center and significant clinical factors). The overall complete response rate for hyperthermia and radiation was 61% compared to 41% for radiation alone. Either Max(TDmin) or Sum(TDmin) were also associated with local disease free survival, time to local failure and overall survival., Conclusions: An earlier report of this trial demonstrated a significant benefit when hyperthermia was added to radiation in the treatment of breast cancer recurrences. The analysis of thermal factors demonstrates that parameters representative of the low end of the measured temperature distributions are associated with initial complete response rate, local disease-free survival, time to local failure and overall survival.

The capability of self-regulating thermoseeds to compensate for nonuniform cooling along their longitudinal axis has been investigated in this study. For this purpose a quasi three-dimensional computer model has been developed. Calculations of the temperature profile in tissue with nonuniform heat loss demonstrated a clear improvement in the longitudinal temperature control of PdNi seeds compared to constant power seeds. Further, two strategies for improved control of nonuniform cooling along the longitudinal axis of ferromagnetic seeds have been investigated: (1) application of a 'normal' undivided seed; and (2) division of a long seed in smaller segments of which each segment is able to respond more directly to local variations in the temperature distribution. Calculations with the quasi three-dimensional model showed that the loose segments do respond more directly to their close proximity. However, the equilibrium temperature of a segment in an area with high local blood flow will be relatively low due the limited heat production of PdNi thermoseeds. In the undivided seeds the high thermal conductivity of PdNi causes some levelling of the longitudinal temperature gradient in the seed. In addition, calorimetric experiments have shown that the heat production of a segmented seed is less effective because of a demagnetizing field. Also, the absence of PdNi between the segments reduces the heat production of the seed.

Background: The biologic rationale for combining cisplatin with locoregional hyperthermia (HT) relates to the potentiating effect of HT on cisplatin cytotoxicity., Methods: Patients with recurrent cervical carcinoma, who had a pelvic recurrence after radiotherapy, were treated with weekly cycles of locoregional HT (using the 70-megahertz, 4 antenna-phased array system for 1 hour and cisplatin, 50 mg/m2 intravenously [i.v.], for a maximum of 12 cycles.), Results: Twenty-three patients were entered in this study. A total of 169 cycles were given. Responses were observed in 12 of 23 patients, a response rate of 52% (95% confidence interval, 31-73%). Salvage surgery became possible in 3 of 12 responding patients, whose tumors were previously considered unresectable. The median duration of response was 9.5+ months, the median overall survival was 8+ months, and the 1-year survival was 42%. No correlation was found between treatment outcome and clinical parameters such as age, weight, performance status, and histology. Thermal parameters such as T20, T50, and T90 were higher in responding patients, but were not significantly different from nonresponding patients. Overall toxicity was moderate. Subcutaneous fatty necrosis due to HT occurred in 10% of the cycles, whereas 2 patients developed skin burns. Squamous cell carcinoma antigen proved to be a valuable tool for the evaluation of response and detection of progression., Conclusions: Weekly locoregional HT and cisplatin, 50 mg/ m2 i.v., for a maximum of 12 cycles was effective treatment in patients with a previously irradiated recurrent carcinoma of the uterine cervix.

In the development of materials for self-regulating thermoseeds much effort is put in improvement of the self-regulating temperature control mechanism of the seeds. The catheters and coatings which are needed to implant the seeds or to guarantee biocompatibility, generally impair the optimized performance of the ferromagnetic seeds. The influence of various coatings on the performance of PdNi seeds has been investigated by means of one-dimensional modelling and calorimetric experiments. Implantation using thin walled catheters is acceptable provided that the catheters are filled with water to assure good thermal coupling. Air layers inside catheters should be avoided as they reduce the sharp gradient of the heat production at the Curie temperature significantly. An alternative for the application of catheters is to insert the seeds into metallic needles. The effect of shielding by the metal needle can be minimized by driving the seed into its saturated state using a high magnetic field strength. The thermal interaction between the seed and surrounding tissue can also be enhanced by placing PdNi, e.g. tubular, on the outside of the catheter or brachytherapy needle. An additional advantage of this new design is an increase in the heat production and the quality of temperature control due to an increase in the amount of PdNi. For permanent implantation seeds can be coated with an inert metal, ceramics or plastic. The performance of the seeds is not affected by any of the coatings if certain conditions are met. For plastic coatings the thickness of the coating has to be very thin, preferably < or = 20 microns, to avoid thermal isolation.

In interstitial hyperthermia using ferromagnetic seeds, multi-filament seeds have gained interest because of a more effective power absorption than solid seeds. Palladium-nickel (PdNi) seeds composed of filaments with diameters in the range from 0.1 to 1.0 mm (maximally 90 filaments) have been investigated to find the conditions for optimal power absorption and temperature control. Magnetic and calorimetric experiments have shown that a decreasing filament radius results in a more effective power absorption. The power absorption approaches a common asymptote for high field intensities at all filament diameters. This asymptotic behaviour can be understood as a consequence of the approach of saturation magnetization of PdNi. The sharpness of the transition at the Curie temperature, which is a measure for the quality of temperature control, improves as the magnetic field strength increases, but it is limited by the asymptote of the power absorption. When the asymptote has been reached the quality of temperature regulation of a seed can only be improved by increasing the amount of PdNi, e.g. by increasing the number of filaments. Calculations of the power absorption, using the generally applied theory based on a linear relation between the magnetization of PdNi and the magnetic field strength, do not correspond quantitatively with experimental results for seeds having an induction number smaller than the 'optimal value' of 2.5. For these seeds the measured heat production is larger than the calculated one.

Purpose: Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed., Methods and Materials: Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials., Results: We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses., Conclusion: The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

The Effective Field Sizes (EFS) and the Effective Heating Depths (EDH) of Contact Flexible Microstrip Applicators (CFMA), tuned at a frequency of 434 MHz, were determined on two fat/muscle phantoms. One phantom was box-shaped with a flat top layer of 1 cm thick artificial fat and the other one a tube of which the cross-section was elliptically shaped (25 x 36 cm) having a fat equivalent shell of 1 cm thick. For the muscle material a 6 g/l saline (NaCl) solution was used. On the flat rectangular phantom, the effective field size at 1 cm depth in saline was measured to be 4.7 x 13.5 cm, 17.5 x 17.7 cm and 12.5 x 14.0 cm for the 1H-applicator, the 3H-applicator and the 5H-applicator, respectively. For the 3H-and the 5H-applicator, the Specific absorption rate (SAR) distribution at 1 cm depth showed a single maximum of SAR for a thin bolus, which split into two separate "hot spots' for a thicker bolus. The Effective Heating Depths in the phantom with a flat surface were of the order of that of a plane wave (approximately 1.4 cm), whereas a larger EHD of 2.4 cm was achieved below the 3H-applicator bent to fit the elliptical phantom. Due to the large effective field size and the "flatness' of the SAR distribution, the applicators 3H and 5H are suitable to adequately treat large superficial tumours.

72 patients with either unresectable or pelvic recurrence of colorectal cancer were treated with combined radiotherapy and locoregional hyperthermia. Radiation doses were 50 Gy or more in patients not previously treated with radiotherapy, and 32 Gy (8 x 4 Gy) in patients who had previously received radiotherapy. Hyperthermia was administered within 30 min of irradiation, and the aim was to give four to six sessions once or twice a week, intending to reach temperatures of at least 41 degrees C over 30 min. The mean of all the minimum (TMIN), maximum (TMAX) and median (TMED) intratumoral temperatures were 39.6, 41.1 and 40.2 degrees C, respectively. Toxicity during hyperthermia treatment consisted mainly of local pain within the heated field (33%) and general discomfort (17%). In 17% of the patients, the hyperthermic treatment was prematurely stopped. Palliation was achieved in 75% of patients with a mean duration of 12 months. The percentage of palliated patients was higher when higher radiation doses were administered. No correlation between palliative effect and thermal parameters was found. A computed tomography scan proved objective remission was obtained in 11 patients (15%). Median survival was 11 months, and 17% of the patients were alive at 3 years. The literature on combined radiotherapy and hyperthermia in colorectal cancer is reviewed. From this review and our own data, it is concluded that thermoradiotherapy is feasible. Acute and late toxicity are not major problems, although pain and general discomfort hamper hyperthermic treatment. The most disappointing fact is that, with the available hyperthermia equipment, the increase in intratumoral temperature does not reach, in general, the therapeutic range.

There are a number of potential advantages to be gained by using an array of applicators in hyperthermia treatments compared with single applicator systems. These advantages include the possibility of greater spatial control of power deposition and conformability to nonplanar sites. Arrays of applicators can be driven either coherently or incoherently. In the case of coherent operation, an added advantage is the ability to steer power deposition by varying the phases of the antennas. In this study, we investigated the relative merits of the two modes of operation when a 2 x 2 planar array of current sheet applicators is used. The effective field size (EFS) of the array was calculated using a Gaussian beam representation of the applicators on a layered model in which the fat layer had its thickness varied. Good agreement was obtained between the square of the electric field distribution (E2) and quantitative experimental results. It is shown that when the planar array is used with a fat layer greater than about 2 mm present, it should be driven incoherently as this results in a significantly larger EFS than that obtained when the array is driven coherently.

An approach to a solution of two major problems in operating Annular Phased Arrays in deep body hyperthermia is presented: an E-field sensor capable of measuring phase and amplitude at 70 MHz and the concept of a power transmission factor to determine the effective amplitude of each applicator. In the four-waveguide Phased Array operating at 70 MHz, which is in clinical use at the department of Radiotherapy of the Academic Medical Center (AMC), the incident fields of the waveguides were scanned in phase and amplitude over the complete aperture midplane, inside an elliptical and a square phantom filled with saline. As a check on the application of the superposition principle, superpositions of the incident fields were compared with the electric field in the measured interference set-ups. With all four applicators radiating at equal amplitude and in phase, the maximum difference over the complete midplane of the phantom between superimposed and measured interference scans was 20% and 10 degrees in the elliptical phantom, and 20% and 30 degrees in the square phantom. After having determined nominal amplitude and phase patterns by a vector probe, any interference set-up can be superimposed from measurement of the actual incident field of each applicator. Therefore, the availability of a vector sensor as described here will contribute to solve a problem of hyperthermia quality assurance: the performance evaluation of Phased Arrays.

Magnetic induction heating of thermoseed implants can be used to produce highly localized hyperthermia in deep-seated tumors. Automatic temperature control throughout the tumor can be achieved by the self-regulating character of ferromagnetic seeds, which corrects for local variations in heat loss due to blood perfusion. An increased sharpness of the ferromagnetic transition at the Curie temperature, Tc, improves the performance of self-regulating control. This was realized for palladium-nickel alloys by a "cold working" procedure preceded and followed by annealing. Palladium-nickel seeds with a predetermined Tc were produced, showing a sharp decrease at Tc of the magnetic susceptibility and the heat production.

The Amsterdam phantom with LED-matrix is applied as an instrument in testing the performance of four types of radiative deep-body hyperthermia systems, which are in clinical use in Germany and The Netherlands. The devices tested were Essen's BSD-1000, Berlin's BSD-2000, Utrecht's Coaxial TEM applicator and Amsterdam's Four-waveguide-array. Photographs were taken of the matrix of dipoles loaded with light-emitting diodes (LED) to visualize the distribution of the RF power deposition or specific absorption rate (SAR) in the aperture midplane. The utility of the phantom with LED matrix for various types of radiative hyperthermia systems is demonstrated. Within this preliminary study, the influence of important parameters on the SAR-pattern in the aperture midplane was demonstrated. After corrections on the phase relation of the applicators a central focus in the SAR distribution could be realized in all systems and could also be moved in any direction. The patterns of the central focus changed in its absolute values and its proportions depending on the relative relations of phase and amplitude of the lateral applicators with respect to the top and bottom applicator. Frequency dependency was recognized for the central focus of the BSD-1000 as well as for the irradiation pattern of a single applicator for the BSD-2000. In the Coaxial TEM applicator it was demonstrated that the dimension of the open water bolus influenced the absolute value of SAR in the aperture midplane.

The utility of the light-emitting diode (LED) matrix, i.e. the qualitative localization of maxima and minima in the patterns of the specific absorption rate (SAR), can be extended to quantitative measurements by a method described. With the LED dipoles on the matrix representing light sources of similar characteristics, the minimal field strength necessary to produce light is a criterion which can be easily determined. From the power levels necessary to fulfil this criterion, relative SAR values have been calculated. The attenuation of field strength by the LED matrix has been measured by an additional dipole antenna with fibre-optic read-out, so that the calculated SAR profiles could be corrected for the relatively smaller attenuation near the edges. This technique has been tested for several set-ups in a 'Coaxial TEM applicator' and the resulting SAR profiles along the major axis of the aperture midplane were compared with SAR profiles determined using a single dipole E-field probe. Results show that, from a set of photographs at different power levels, SAR profiles can be constructed with limited accuracy along lines in any direction in the whole aperture midplane and by this the complete two-dimensional SAR pattern can be obtained.

The cervical region of the rat, including the spinal cord (cervical 5-thoracic 2) was irradiated with single doses of 15-32 Gy 250 kV X-rays. Hyperthermia, at temperatures of 42-, 43- and 44 +/- 0.1 degrees C for 30 min was applied to the cervical vertebral column and immediate adjacent tissues for 5-10 min or 7 h after X-irradiation. Over a period of 18-21 months, animals were followed up to monitor neurological complications occurring as a result of damage to the spinal cord (Sminia et al. 1991). We also noted the development of neoplasms either inside or outside the cervical region. The data on tumour incidence were analysed retrospectively using the actuarial method. Although hyperthermia alone was not carcinogenic, it led to a significant increase of radiation-induced tumours. This increase of radiation carcinogenesis was observed both with hyperthermia applied 5-10 min after X-rays and with an interval of 7 h between X-rays and heat. Cancer induction was highest after the lower radiation doses (16 Gy) combined with high heat doses (30 min 44 degrees C). The latent period for induction of tumours by X-rays was 472 +/- 19 days (mean +/- SEM; n = 24). Latency was significantly shortened by hyperthermia to 404 +/- 34 days (n = 22) if applied 5-10 min after X-rays and to 348 +/- 6 days (n = 33) with an interval of 7 h. Histology revealed that 86% (38/44) of the examined tumours found inside the volume treated with hyperthermia and irradiation were sarcomas. The percentage of animals with a tumour outside the treated volume was almost the same for all treatment groups. Most of these tumours were of the mammary gland type.

An experimental study is described, leading to the design of a near-field electromagnetic radiation probe. A passive field probe with fibre-optic link has been constructed for use in hyperthermia phantoms, i.e. for measurements in lossy media--saline was used in this study as a simulation of biological tissue. The realization of a closed electric circuit on the probe proved to be a major influence on the sensitivity and dynamic range of the probe. The experiments also independently confirmed the dipole length, frequency variations between 5 and 110 MHz and the temperature of the probe as important parameters.

A simple, unique tool has been constructed at a very low cost for visualization of the electric field distribution in a phantom exposed to radiofrequency fields from a four-applicator hyperthermia system. The tool consists of a thin Perspex plate to which light-emitting diodes (LEDs) have been attached in a regular pattern. The leads of these LEDs have been bent in the form of dipoles. Electric field distributions can be made visible, because the light intensity from an individual LED dipole in a RF field is a function of the local electric field strength. The LED dipoles were arranged in a 11 x 15 matrix with a mutual distance of 2 cm. Experiments have been performed in a cylinder with a length of 100 cm and with an elliptical cross-section of 24 cm x 36 cm. The cylinder was filled with saline to simulate the electric properties of biological tissue. The matrix plate was shaped like the cross-section inside the phantom, and could be moved to any position under the externally applied antennae. In our department the applicators installed form a system of four coherent waveguide radiators operating at a frequency of 70 MHz. Photographs have been taken from the distribution of the light intensity through transparent windows at the outer ends of the phantom. The advantage of the LED matrix is the fact that the effect of changing phase relations, amplitudes or position of any applicator on the electric field distribution can be seen instantaneously. The interference effects of multiple fields, i.e. extinction and reinforcement, become easily visible. Typical examples demonstrate the necessity to obtain the field distribution not only along some previously chosen lines, but in the whole transversal midplane. The attenuation of field strength due to the presence of the matrix varies only slightly from the edge to the centre of the matrix, so the pattern of light intensity is in good qualitative agreement with the pattern of field strength. The LED matrix has been very useful in the verification of pretreatment planning calculations, and is already used for intercomparison and evaluation studies of similar hyperthermia equipment.

In 24 patients with metastatic malignant melanoma, combined treatment with radiation and hyperthermia was administered to 38 localizations, radiation alone to 8 comparative localizations and hyperthermia alone to 3 localizations. Hyperthermia was administered during one hour by using a 433 MHz microwave generator. The heat treatment was given within 30 min following irradiation. Although an intratumoral temperature of 43 degrees C was aimed, considerable variations occurred during one session and from session-to-session. Radiation schedules consisted in either one large fraction (6-8 Gy) once a week in 14-21 days or two fractions (4-5 Gy) twice a week in 21 days. In the group of patients receiving irradiation once a week, three heat treatments were administered. In the twice-a-week radiation schedule, six heat sessions were given. The overall complete response (CR) rate in patients receiving combined treatment was 50%. In the group of patients treated with hyperthermia and irradiation schedules of 8 Gy per fraction, the CR rate was 83%. Irradiation alone achieved 38% CR rate but some of these CR relapsed during follow-up whereas the comparative area treated with radiation and heat remained under control at this time. The lesions treated with heat alone did not show any response to treatment. Enhancement of the acute skin reactions was generally observed. However, because the total doses were relatively low, this enhancement did not constitute a clinical problem. CR appears to occur more frequently in small tumor sizes. The highest and lowest temperature ever registered during any session of hyperthermia did not seem to correlate with the tumor response.

In 35 patients with chestwall recurrences of breast carcinoma, 45 lesions were treated with combined radiation and hyperthermia. The majority of the lesions received 6 fractions of 4 Gy, twice a week during 3 weeks. Hyperthermia was administered within 30 min after irradiation, aiming a tumor temperature of 43 degrees C during one hour. The percentage of complete response (CR) was 57%. In small lesions, the percentage of CR was 80%. The mean duration of the response was 7 months. Response rate increased with increasing temperature. Particularly, mean temperature and isoeffect thermal dose correlated very well with response rate. In nine cases, comparative lesions were treated with either radiation alone or radiation combined with hyperthermia. The response rates were 3/9 and 7/9, respectively. Acute skin reactions were enhanced by the combined treatment. However, late skin reactions were not increased. Although the prognosis of patients with chestwall recurrences is determined by the presence of distant metastases, local control remains an important objective. Combined treatment with radiation and hyperthermia offers the possibility of obtaining a high local control rate particularly in relatively small lesions.

Hyperthermia was applied in the region of the vertebral column between the cervical vertebrae 5 and thoracic 2, using a ring-shaped applicator operating at a microwave frequency of 434 MHz. This region was focally heated, including spinal cord, vertebrae, intervertebral discs and nerve roots. In all experiments temperature was measured at a 'reference' thermocouple probe which was placed against one of the cervical vertebrae 6, 7 or thoracic 1. Temperatures inside the vertebral canal were measured separately and proved to be below the 'reference' temperature: at 42 degrees, 43 degrees, 44 degrees and 45 degrees C (+/- 0.1 degree C) respectively the temperature in the canal was 41.2 degrees, 42.3 degrees, 42.9 degrees and 43.2 degrees C (+/- 0.4 degree C). Temperatures in tissues close to the vertebrae (e.g. within 2 mm lateral to the vertebrae, in the region of the brachial plexus) did not differ significantly from the temperature inside the canal. The temperature inside the intervertebral disc was as high as the 'reference' temperature. Temperatures measured at other sites, e.g. in the oesophagus, rectally and in the cervical muscles 5 or 10 mm lateral from the vertebral column showed that these sites were only slightly heated. The effects of hyperthermia at temperatures inside the spinal canal ranging from 41.2-43.2 degrees C for 30-120 min were investigated. One day after treatment at 41.2 degrees C for 120 min or 42.3 degrees C for 60 min neither neurological symptoms nor deaths were observed. Minor neurological symptoms were observed one day after 75 min at 42.3 degrees C. The incidence and severity of the neurological symptoms (ranging from unco-ordinated use of the forelegs to paralysis) increased with increasing temperature and duration of the hyperthermic treatment. Thermal damage even resulted in lethality: 74 per cent of the rats that died did so between 2 and 42 h after treatment. The LD50 value at 60 days at 43.2 degrees C was 30 min, at 42.9 degrees C, 41 min, and at 42.3 degrees C, 92 min. In most rats with neurological symptoms after treatment, recovery from motor dysfunctions took place within about two weeks. Even severe neurological symptoms which did not lead to lethality recovered completely. At day 60 no neurological symptoms were observed.