J. Crezee

Temperature uniformity during hyperthermia: the impact of large vessels

During hyperthermia the presence of a large vessel entering the heated volume and carrying blood at the systemic temperature can be an important source of temperature non-uniformity and possible underdosage. The minimal tumour temperature near a large vessel is determined by the vessel wall temperature: a number of factors influencing the vessel wall temperature are considered--effective tissue conductivity, flow type, vessel size, entrance effects and counter-current flow. In some specific cases, especially when tissue perfusion is high, the vessel wall temperature may reach therapeutic levels when the mean blood temperature is still low. In general, well perfused tumours have a better chance of being heated uniformly. Regional heating improves temperature uniformity by reducing entrance and equilibration effects as blood is heated before entering the tumour. Raising the core temperature also reduces temperature inhomogeneity. Spatial SAR resolution should preferably be of the order of magnitude of a centimetre or better.

Experimental verification of bioheat transfer theories: measurement of temperature profiles around large artificial vessels in perfused tissue

The verification of thermal models for use in hyperthermia treatment planning is essential. We investigated the heat transfer between a single vessel and the surrounding vascularised tissue, comparing the conventional bioheat transfer theory and the recently developed keff model using analytical and numerical methods. A plastic tube inserted into the tissue of an isolated perfused organ served as an artificial vessel. This enabled us to vary the blood flow in the vessel and in the tissue independently. The organ used was a bovine kidney, turned into a perfused tissue phantom using an alcohol fixation technique. The temperature profile within the tissue was mapped with constantan-manganin thermocouple wire sensors with a total diameter of 50 microns. The temperature profile relative to the temperature difference between the vessel and organ was measured; increased perfusion caused a reduction of the vessel wall temperature but did not affect the width of the profile. Studying the transient tissue temperature after a step-wise change of the blood temperature in the vessel revealed a faster diffusion of heat at higher perfusion rates. These facts are in accordance with the keff model, but not with the conventional heat-sink theory.

Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all.

The currently available arsenal of anticancer modalities includes many DNA damaging agents that can kill malignant cells. However, efficient DNA repair mechanisms protect both healthy and cancer cells against the effects of treatment and contribute to the development of drug resistance. Therefore, anti-cancer treatments based on inflicting DNA damage can benefit from inhibition of DNA repair. Hyperthermia – treatment at elevated temperature – considerably affects DNA repair, among other cellular processes, and can thus sensitize (cancer) cells to DNA damaging agents. This effect has been known and clinically applied for many decades, but how heat inhibits DNA repair and which pathways are targeted has not been fully elucidated. In this review we attempt to summarize the known effects of hyperthermia on DNA repair pathways relevant in clinical treatment of cancer. Furthermore, we outline the relationships between the effects of heat on DNA repair and sensitization of cells to various DNA damaging agents.

The theoretical and experimental evaluation of the heat balance in perfused tissue

Accurate treatment planning is necessary for the successful application of hyperthermia in the clinic. The validity of four different bioheat models or combinations of models is evaluated: the conventional bioheat transfer equation, the limited effective conductivity model, a mixed heat sink-effective conductivity model and a discrete vessel model. The heat balance for the heated volume, and especially the ratio between conductive heat removal and heat escape through the veins, is different for each of these models. Model predictions were compared with results from experiments on isolated perfused bovine tongues. Tongues were suspended in a water-filled container and heated by conduction. The steady state temperature distribution and heat balance were determined at various blood flow rates. Increased blood flow was found to lower the mean tissue temperature and to enhance both conductive and venous heat removal. This result agrees only with the mixed heat sink-effective conductivity and the discrete vessel model predictions. At low flow rates a modified heat sink term should be used because the venous efflux temperature was significantly lower than the mean tissue temperature.

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.

Cell survival and radiosensitisation: modulation of the linear and quadratic parameters of the LQ model (Review).

The linear-quadratic model (LQ model) provides a biologically plausible and experimentally established method to quantitatively describe the dose-response to irradiation in terms of clonogenic survival. In the basic LQ formula, the clonogenic surviving fraction Sd/S₀ following a radiation dose d (Gy) is described by an inverse exponential approximation: Sd/S₀ = e-(αd+βd²), wherein α and β are experimentally derived parameters for the linear and quadratic terms, respectively. Radiation is often combined with other agents to achieve radiosensitisation. In this study, we reviewed radiation enhancement ratios of hyperthermia (HT), halogenated pyrimidines (HPs), various cytostatic drugs and poly(ADP-ribose) polymerase‑1 (PARP1) inhibitors expressed in the parameters α and β derived from cell survival curves of various mammalian cell cultures. A significant change in the α/β ratio is of direct clinical interest for the selection of optimal fractionation schedules in radiation oncology, influencing the dose per fraction, dose fractionation and dose rate in combined treatments. The α/β ratio may increase by a mutually independent increase of α or decrease of β. The results demonstrated that the different agents increased the values of both α and β. However, depending on culture conditions, both parameters can also be separately influenced. Moreover, it appeared that radiosensitisation was more effective in radioresistant cell lines than in radiosensitive cell lines. Furthermore, radiosensitisation is also dependent on the cell cycle stage, such as the plateau or exponentially growing phase, as well as on post-treatment plating conditions. The LQ model provides a useful tool in the quantification of the effects of radiosensitising agents. These insights will help optimize fractionation schedules in multimodality treatments.

Accelerated ray tracing for radiotherapy dose calculations on a GPU

PURPOSE The graphical processing unit (GPU) on modern graphics cards offers the possibility of accelerating arithmetically intensive tasks. By splitting the work into a large number of independent jobs, order-of-magnitude speedups are reported. In this article, the possible speedup of PLATOs ray tracing algorithm for dose calculations using a GPU is investigated. METHODS A GPU version of the ray tracing algorithm was implemented using NVIDIAs CUDA, which extends the standard C language with functionality to program graphics cards. The developed algorithm was compared based on the accuracy and speed to a multithreaded version of the PLATO ray tracing algorithm. This comparison was performed for three test geometries, a phantom and two radiotherapy planning CT datasets (a pelvic and a head-and-neck case). For each geometry, four different source positions were evaluated. In addition to this, for the head-and-neck case also a vertex field was evaluated. RESULTS The GPU algorithm was proven to be more accurate than the PLATO algorithm by elimination of the look-up table for z indices that introduces discretization errors in the reference algorithm. Speedups for ray tracing were found to be in the range of 2.1-10.1, relative to the multithreaded PLATO algorithm running four threads. For dose calculations the speedup measured was in the range of 1.5-6.2. For the speedup of both the ray tracing and the dose calculation, a strong dependency on the tested geometry was found. This dependency is related to the fraction of air within the patients bounding box resulting in idle threads. CONCLUSIONS With the use of a GPU, ray tracing for dose calculations can be performed accurately in considerably less time. Ray tracing was accelerated, on average, with a factor of 6 for the evaluated cases. Dose calculation for a single beam can typically be carried out in 0.6-0.9 s for clinically realistic datasets. These findings can be used in conventional planning to enable (nearly) real-time dose calculations. Also the importance for treatment optimization techniques is evident.

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.

Hyperthermia, cisplatin and radiation trimodality treatment: a promising cancer treatment? A review from preclinical studies to clinical application.

This review discusses available clinical and experimental data and the underlying mechanisms involved in trimodality treatment consisting of hyperthermia, cisplatin and radiotherapy. The results of phase I/II clinical trials show that trimodality treatment is effective and feasible in various cancer types and sites with tolerable toxicity. Based on these results, phase III trials have been launched to investigate whether significant differences in treatment outcome exist between trimodality and standard treatment. In view of the clinical interest, it is surprising to find so few preclinical studies on trimodality treatment. Although little information is available on the doses of the modalities and the treatment sequence resulting in the largest degree of synergistic interaction, the results from in vivo and in vitro preclinical studies support the use of trimodality treatment for cancer patients. Animal studies show an improvement in treatment outcome after trimodality treatment compared with mono- and bimodality treatment. Studies in different human tumour cell lines show that a synergistic interaction can be obtained between hyperthermia, cisplatin and radiation and that this interaction is more likely to occur in cell lines which are more sensitive to cisplatin.

Optimization in hyperthermia treatment planning: The impact of tissue perfusion uncertainty

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