Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future.

Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45°C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities.

Delineation of potential hot spots for hyperthermia treatment planning optimisation.

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.

A feasibility study in oesophageal carcinoma using deep loco-regional hyperthermia combined with concurrent chemotherapy followed by surgery.

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.

A feasibility study of interstitial hyperthermia plus external beam radiotherapy in glioblastoma multiforme using the Multi ELectrode Current Source (MECS) system.

PURPOSE: Thermoradiotherapy has been shown in several randomized trials to increase local control compared to radiotherapy alone. The first randomized study of interstitial hyperthermia in glioblastoma multiforme showed a survival benefit for hyperthermia, though small. Improvement of the heating technique could lead to improved results. The purpose of this feasibility study is to present the clinical and thermal data of application of an improved interstitial hyperthermia system. METHODS AND MATERIALS: Six patients with a glioblastoma multiforme were treated with interstitial hyperthermia using the Multi Electrode Current Source Interstitial Hyperthermia (MECS-IHT) system. The MECS-IHT system has the capability of spatial monitoring of temperature and individually steering of heating electrodes. Three sessions were given aiming at a steady state temperature of 42 degrees C for 1 h, with an interval of 3-4 days, during an external irradiation scheme of 60 Gy in 6 weeks. Hyperthermia was delivered with a mean of 10 catheters, 18 heating electrodes and 38 thermal probes per patient. RESULTS: Sub-optimal temperatures were encountered in the first two patients leading to adjustments in technique thereafter with subsequent improvement of thermal data. With a catheter spacing of 11-12 mm, measurements yielded a mean T(90), T(50) and T(10) of 39.9, 43.7 and 45.2 degrees C, respectively, over three sessions in the last patient. The power per electrode to reach this temperature distribution varied from 25-100% of full power in each of the last four patients. Thermal data were reproducible over the three sessions. Acute toxicity was minimal. CONCLUSIONS: Despite the spatial steering capabilities of the MECS-IHT system, a large temperature heterogeneity was encountered. The heterogeneity was the reason to limit the catheter spacing to 11-12 mm, thus making only small tumour volumes feasible for interstitial heating.

Clinical thermometry, using the 27 MHz multi-electrode current-source interstitial hyperthermia system in brain tumours.

BACKGROUND AND PURPOSE: In interstitial hyperthermia, temperature measurements are mainly performed inside heating applicators, and therefore, give the maximum temperatures of a rather heterogeneous temperature distribution. The problem of how to estimate lesion temperatures using the multi-electrode current-source interstitial hyperthermia (MECS-IHT) system in the brain was studied. MATERIALS AND METHODS: Temperatures were measured within the electrodes and in an extra catheter at the edge of a 4 x 4 x 4.5 cm(3) glioblastoma multiforme resection cavity. From the temperature decays during a power-off period, information was obtained about local maximum and minimum tissue temperatures. The significance of these data was examined through model calculations. RESULTS: Maximum tissue temperatures could be estimated roughly by switching off all electrodes for about 5 s. Model calculations showed that the minimum tissue temperatures near a certain afterloading catheter correspond well with the temperature of the applicator inside, about 1 min after this applicator was switched off. CONCLUSIONS: Although the electrode temperatures read during heating are not suitable to assess the temperature distribution, it is feasible to heat the brain adequately using the MECS-IHT system with extra sensors outside the electrodes and/or application of decay methods.

Temperature measurement errors with thermocouples inside 27 MHz current source interstitial hyperthermia applicators.

The multielectrode current source (MECS) interstitial hyperthermia (IHT) system uses thermocouple thermometry. To obtain a homogeneous temperature distribution and to limit the number of traumas due to the implanted catheters, most catheters are used for both heating and thermometry. Implications of temperature measurement inside applicators are discussed. In particular, the impact of self-heating of both the applicator and the afterloading catheter were investigated. A one-dimensional cylindrical model was used to compute the difference between the temperature rise inside the applicators (deltaTin) and in the tissue just outside the afterloading catheter (deltaTout) as a function of power absorption in the afterloading catheter, self-heating of the applicator and the effective thermal conductivity of the surrounding tissue. Furthermore, the relative artefact (ERR), i.e. (deltaTin - deltaTout)/deltaTin, was measured in a muscle equivalent agar phantom at different positions in a dual-electrode applicator and for different catheter materials. A method to estimate the tissue temperature by power-off temperature decay measurement inside the applicator was investigated. Using clinical dual-electrode applicators in standard brachytherapy catheters in a muscle-equivalent phantom, deltaTin is typically twice as high as deltaTout. The main reason for this difference is self-heating of the thin feeder wires in the centre of the applicator. The measurement error caused by energy absorption in the afterloading catheter is small, i.e. even for materials with a high dielectric loss factor it is less than 5%. About 5 s after power has been switched off, Tin in the electrodes represents the maximum tissue temperature just before power-off. This delay time (t(delay)) and ERR are independent of Tin. However, they do depend on the thermal properties of the tissue. Therefore, ERR and t(delay) and their stability in perfused tissues have to be investigated to enable a reliable estimation of the tissue temperatures around electrodes in clinical practice.

Spatial temperature control with a 27 MHz current source interstitial hyperthermia system.

PURPOSE: This article gives an overview of the properties of a 27 MHz current source interstitial hyperthermia system, affecting temperature uniformity. METHODS AND MATERIALS: Applicators can be inserted in standard flexible afterloading catheters. Maximum temperatures are measured with seven-point constantan-manganin thermocouple probes inside each applicator. Temperature can be controlled automatically using a simple control algorithm. Three-dimensional power absorption and thermal models for inhomogeneous tissues are available to optimize applicator geometry and phase configuration. Properties of the interstitial heating system have been verified both in phantom experiments and in in vivo treatments of rhabdomyosarcomas implanted in the flank of a rat. RESULTS: An experiment with four electrodes in one catheter proves that longitudinal control of the specific absorption rate (SAR) is feasible. Local cooling applied by cold water circulation through a catheter perpendicular to the afterloading catheter could be compensated by independent control of electrode power. Furthermore, comparison of two different phase configurations using four dual electrode applicators shows that the SAR distribution can be manipulated significantly, utilizing the phase of the electrodes. Finally, the temperature can be controlled safely and model calculations are in fair agreement with the measurements. CONCLUSIONS: The features of the 27 MHz current source interstitial hyperthermia system enable spatial temperature control at approximately 1.5 cm.

A description of discrete vessel segments in thermal modelling of tissues.

In hyperthermia treatment planning vessels with a diameter larger than 0.5 mm must be treated individually. Such vessels can be described as 3D curves with associated diameters. The temperature profile along the vessel is discretized one dimensionally. Separately the tissue is discretized three dimensionally on a regular grid of voxels. The vessel as well as the tissue are positioned in one global space. Methods are supplied to describe the tissue-vessel interaction, the shift of the blood temperature profile describing the flow of blood along the vessel and the calculation of the vessel wall temperature. The calculation of the interaction is based on tissue temperature samples and the blood temperature together with the distance between the centre of the vessel and the tissue temperature sample. An analytical expression for a vessel inside a coaxial tissue cylinder is then used for the calculation of the heat flow rate across the vessel wall. The basic test system is a vessel segment embedded inside a coaxial tissue cylinder. All the tests use this setup while the following simulation parameters are varied: position and orientation of the vessel relative to the tissue grid, vessel radius, sample density of the blood temperature and power deposition inside the tissue cylinder. The blood temperature profile is examined by calculation of the local estimate of the equilibration length. All tests show excellent agreement with the theory.