Thermotherapy of Prostate Cancer Using Magnetic Nanoparticles: Feasibility, Imaging, and Three-Dimensional Temperature Distribution

Transcription

1 european urology 52 (2007) available at journal homepage: Prostate Cancer Thermotherapy of Prostate Cancer Using Magnetic Nanoparticles: Feasibility, Imaging, and Three-Dimensional Temperature Distribution Manfred Johannsen a, *,1, Uwe Gneveckow c,1, Burghard Thiesen b, Kasra Taymoorian a, Chie Hee Cho b, Norbert Waldöfner c, Regina Scholz c, Andreas Jordan c, Stefan A. Loening a, Peter Wust b a Department of Urology, Campus Mitte, Charité-Universitätsmedizin, Berlin, Germany b Department of Radiology, Campus Virchow-Klinikum, Charité-Universitätsmedizin, Berlin, Germany c MagForce Nanotechnologies AG, Berlin, Germany Article info Article history: Accepted November 9, 2006 Published online ahead of print on November 17, 2006 Keywords: Magnetic Nanoparticles Prostate cancer Thermotherapy Abstract Objectives: To investigate the feasibility of thermotherapy using biocompatible superparamagnetic nanoparticles in patients with locally recurrent prostate cancer and to evaluate an imaging-based approach for noninvasive calculations of the three-dimensional temperature distribution. Methods: Ten patients with locally recurrent prostate cancer following primary therapy with curative intent were entered into a prospective phase 1 trial. The magnetic fluid was injected transperineally into the prostates according to a preplan. Patients received six thermal therapies of 60-min duration at weekly intervals using an alternating magnetic field applicator. A method of three-dimensional thermal analysis based on computed tomography (CT) of the prostates was developed and correlated with invasive and intraluminal temperature measurements. The sensitivity of nanoparticle detection by means of CT was investigated in phantoms. Results: The median detection rate of iron oxide nanoparticles in tissue specimens using CT was 89.5% (range: 70 98%). Maximum temperatures up to 55 8C were achieved in the prostates. Median temperatures in 20%, 50%, and 90% of the prostates were C (range: C), C (range: C), and C (range: C), respectively. Median urethral and rectal temperatures were C (range: C) and C (range: C). The median thermal dose was 7.8 (range: ) cumulative equivalent minutes at 43 8C in 90% of the prostates. Conclusion: The heating technique using magnetic nanoparticles was feasible. Hyperthermic to thermoablative temperatures were achieved in the prostates at 25% of the available magnetic field strength, indicating a significant potential for higher temperatures. A noninvasive thermometry method specific for this approach could be developed, which may be used for thermal dosimetry in future studies. # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Campus Mitte, Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin, Germany. Tel ; Fax: address: manfred.johannsen@charite.de (M. Johannsen). 1 M.J. and U.G. contributed equally to this manuscript /$ see back matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 1654 european urology 52 (2007) Introduction Dispersions of biocompatible iron oxide nanoparticles in water (magnetic fluids) can be injected into tumours and heated in an externally applied alternating magnetic field by brownian and Néel relaxation processes [1,2]. The large number and overall surface of magnetic elements within such fluids result in excellent power absorption capabilities, which makes them particularly suitable for contactless, selective interstitial heating of tumours [3]. Animal studies on mouse mammary carcinoma, glioblastoma, and prostate cancer have demonstrated the feasibility and efficacy of this heating method as well as a very low clearance rate of these nanoparticles from tumours, allowing for serial heat treatments following a single magnetic fluid injection [4 8]. We conducted the first clinical trial to evaluate this technology in patients with recurrent prostate cancer. There is currently no standard therapy for locally recurrent disease [9]. Treatment options include androgen deprivation, salvage radical prostatectomy, salvage brachytherapy, and cryotherapy [10]. An important prerequisite for treatment planning and quality control in thermal therapy using magnetic nanoparticles is adequate imaging. Magnetic resonance imaging (MRI) cannot be used because of signal void in the areas containing a high concentration of iron oxide nanoparticles. Transrectal ultrasound (TRUS) is suitable for imaging of the prostate, but not for visualisation of magnetic nanoparticles. Deposits of these particles in phantoms and prostate tissue can be visualised by computed tomography (CT) [11,12]. However, the sensitivity of CT to quantitatively detect the injected nanoparticles has not been determined so far. The current study investigated the feasibility of magnetic nanoparticle thermotherapy, defined as the ability to attain at least hyperthermic temperatures in the prostates at the maximum field strength tolerated for 60 min without signs of toxicity, to achieve sufficiently durable interstitial deposition and homogeneous distribution of nanoparticles in the prostates to allow for six thermal treatments at weekly intervals and to evaluate the suitability of a CT-based approach for quality control and noninvasive thermal analysis by a correlation with invasive temperature measurements. 2. Patients, materials, and methods 2.1. Patients Ten patients with biopsy-proven locally recurrent prostate cancer were entered into a prospective phase 1 study. Patients were either not suitable for or refused salvage radical prostatectomy. End points of this study were the feasibility of both thermal treatment and thermal analysis. Detailed patient characteristics, toxicity, quality of life, and oncologic outcome are subject of a separate report Treatment planning and injection of magnetic fluid The nanoparticles used in this study had an average core size of 15 nm and were coated with an aminosilane-type shell (MFL AS, MagForce 1 Nanotechnologies, Berlin, Germany). Concentration of ferrites in aqueous solution was 112 mg/ml. Treatment planning was based on thin-sliced (2.5-mm) CT Fig. 1 Three-dimensional reconstructed image of the prostate, viewed from below, illustrating a simplified preplan (left; prostate volume in green, spline probes in red). The three-dimensional image indicates the planned position of the trajectories, where the nanoparticle dispersion is ideally distributed as a continuous deposit moving the needle from the basal to the apical end of the prostate (0.5 1 ml/trajectory). A three-dimensional image of the same patient is shown after the magnetic fluid injection (center; nanoparticle deposits in blue). In the native computed tomography scan of the same patient (right), iron oxide nanoparticle deposits in the prostate appear as regions of higher density compared to the surrounding prostate tissue. Isothermic lines describe calculated intraprostatic temperatures.

3 european urology 52 (2007) scans of the prostate. Using the newly developed software module NanoPlan 1 (MagForce Nanotechnologies, Berlin, Germany) in combination with the visualisation package AMIRA (Mercury Computer Systems, Berlin, Germany), threedimensional CT reconstruction images of the prostate were obtained and the number and position of the magnetic fluid deposits required for sufficient heat deposition in the prostate were calculated on the basis of the known specific absorption rate (SAR) of magnetic nanoparticles and the estimated perfusion (Fig. 1). The patients were placed in the lithotomy position and the nanoparticle dispersion was injected transperineally into the prostate under general anaesthesia and TRUS/fluoroscopy guidance using a template and a 20-gauge needle according to the preplan [12]. Four closed-end catheters were placed in the prostate for thermometry (two in each lobe). Native CT scans were repeated after nanoparticle injection to visualise the distribution of nanoparticles in the prostates and allow for temperature calculations (Fig. 1). Insertion of four closed-end catheters for invasive thermometry was repeated before the last treatment 6 wk later. Patients were placed in the alternating magnetic field applicator and fiberoptic thermometry probes (Luxtron, Santa Ana, CA, diameter 0.5 mm accuracy: 0.3 8C) were positioned in the prostate, urethra, rectum, perineum, scrotum, and left ear. A cooling device was positioned in both groins and the perineum and connected to a water pump [12] CT experiments in tissue phantoms Equal volumes of undiluted magnetic fluid (0.5 ml) were injected into 20 identical tissue samples (pork meat). Two samples were not injected and served as controls to establish baseline CT density. The samples were placed in a CT scanner and native scans using thin slices (0.6 mm) were performed. Magnetic nanoparticle deposits appeared as regions with higher density compared to the surrounding tissue, expressed in Hounsfield units (HU). At a density (g/ml iron) of >10 g/l iron, which corresponds to a dilution of more than 10:1 of the original magnetic nanoparticle suspension, these depots are well recognised in gel phantoms [11]. Using the AMIRA software, the three-dimensional nanoparticle deposits were visualised and contoured. According to the HU values, the iron mass in each tissue sample was calculated Thermotherapy Treatments were delivered in the magnetic field applicator MFH 1 300F (MagForce Nanotechnologies), using an alternating magnetic field with a frequency of 100 khz and a variable field strength of ka/m. This system has recently been characterised and described in detail [11]. The first thermotherapy session was performed 1 2 h after magnetic fluid injection (under general anaesthesia) with the patient fully awake, to monitor treatment tolerance and sideeffects during the heat treatment. Thermotherapy was started at a magnetic field strength of 2.5 ka/m, which was gradually increased as tolerated without discomfort and kept constant for 60 min, aiming for an intratumoural temperature of C. Instead of a fixed thermal goal, we aimed to evaluate the maximum field strength tolerated for 60 min without signs of toxicity in individual patients, as long as urethral and rectal temperatures were 43 8C. Urethral cooling was carried out if this temperature was exceeded. Temperatures in the thermosensors were monitored online by an application software (MagForce Nanotechnologies) and adjusted as desired or tolerated by the patient by modulating the alternating magnetic field strength. Six thermotherapy sessions took place at weekly intervals Invasive thermometry and temperature calculations Thermometry was carried out invasively in the prostate during the first and last thermotherapy session and intraluminally in the urethra and in the rectum during each treatment. Additional superficial temperature measurements were performed on the skin of the perineum, scrotum, and left ear during each session. Temperature mapping in the prostate, urethra, and rectum was carried out at least once during treatment by pulling the probes in 5-mm steps from the most cranial position in caudal direction until skin level. The urethral catheter was closed with a clamp before temperature measurements were made. The exact position of each thermometry catheter track in the prostate was verified by CT and only measurements inside the prostate were included in the thermal analysis. Temperature distribution in the target region was calculated from the iron mass (derived from nanoparticle volume and density in CT), the strength of the magnetic field during treatments, and the known SAR of the magnetic fluid used (assuming a constant perfusion) by solving the bio-heat transfer equation. This differential equation was solved on the basis of the finite element method. The three-dimensional temperature distribution was visually fitted to the measurements in the reference points of the implanted thermometry catheters by selecting an appropriate average perfusion (called virtual perfusion [VP]) in the bio-heat transfer equation. An example of the temperature curves obtained, supplemented by the calculated temperatures, is given in Fig Thermal dose calculation Temperatures are given as maximum values, T 20,T 50,and T 90 (temperatures exceeded in 20%, 50%, or 90% of the prostate). The total thermal dose is expressed as the cumulative equivalent minutes at 43 8C achieved or exceeded in 90% of the prostate (CEM 43 8C T 90 ), summed up for each thermotherapy session during the course of treatment. The underlying principle of an isoeffect relationship between different temperatures (Arrhenius relationship) takes into account that intratumoural temperatures are not uniform and that time-temperature data vary from patient to patient. It is expressed by the formula: CEM 43 8C =tr (43 T),withCEM 43 being the cumulative equivalent minutes at 43 8C, equivalent to a temperature T for the time t. Theconstant R is 0.25 for T < 43 8C and0.5fort > 43 8C. For example, to achieve an equivalent thermal cell-killing effect compared to 43 8C, a 4-fold longer heating at 42 8C,butonlyhalfofthe heatingtimeat448cwould be required [13]. This thermal dose concept has been validated in prospective randomised studies [14,15].

4 1656 european urology 52 (2007) Fig. 2 Samples of temperature curves obtained during thermotherapy treatment. Temperature mapping was done by moving the temperature probe stepwise from the basis to the apex of the prostate until skin level (from left to right in the images). Four individual temperature curves during the treatment of one patient are shown (A D). The tips of the thermometry sensors were located at the basis of the prostate (not all at the same level). The dotted lines represent invasively measured temperatures in the prostate. The continuous lines represent calculated temperatures in the corresponding regions. In the prostate, a reasonable agreement between noninvasive temperature calculations and invasive thermometry was observed (left). At the skin level (between 7 and 10 cm), relative peaks of measured, but not calculated, temperatures can be seen despite the absence of nanoparticles. These undesired temperature elevations are due to power deposition of the magnetic field in superficial regions, for example, superficial currents. (E) Temperature curves of the urethra and rectum during the same treatment.

5 Table 1 Example of integrated nanoparticle imaging parameters and thermal analysis data set available for each patient (AMIRA software and MagForce NanoPlan W module) Patient no. Injected amount magnetic fluid, ml Total no. of sessions Target volume, ml Heat session FS, ka/m VP, ml/ 100g/min HU NPV CT, ml SAR NPV, W/kg T max measured, 8C T max calculated, 8C T 20 calculated, 8C T 50 calculated, 8C T 90 calculated, 8C CEM 43 8C T 90, min mean mean mean mean mean mean mean mean mean mean Mean Median All indicated temperatures refer to the prostate. FS = field strength; VP = virtual perfusion; HU = Hounsfield units; NPV CT = nanoparticle volume in computed tomography; SAR NPV = mean specific absorption rate achieved in the region of the nanoparticles defined by HU >75; T 20, T 50, T 90 = temperature exceeded in 20%, 50%, and 90% of the prostate; CEM 43 8C T 90 = cumulative equivalent minutes at 43 8C in 90% of the prostate (thermal dose). european urology 52 (2007)

6 1658 Temperatures between 40 8C and 45 8C are generally being referred to as hyperthermia. Temperatures of up to 42 8C can render cancer cells more susceptible to the effects of irradiation and cause a certain degree of apoptosis, whereas temperatures >45 8C are termed thermoablation and cause direct cell killing [1]. Knowledge of the intratumoural temeuropean urology 52 (2007) Results 3.1. Treatment planning The procedure of TRUS-guided magnetic fluid injection according to the preplan was feasible in all patients. Because, at present, no system is available for direct CT-guided magnetic fluid injection under real-time visual control, a three-dimensional reconstruction of the TRUS images of the prostates was performed prior to the injection procedure and compared to the CT data. In two cases, the plan was adjusted because of small variations of the prostate contour caused by positioning of the patient. In general, it was found that prostate tissue irradiated previously offered considerable mechanical resistance to the injection and probably also to the intraprostatic diffusion of the magnetic fluid. Thus, the optimal (precalculated) distribution of magnetic nanoparticles in the target region could not be achieved (Fig. 1) Detection of nanoparticles in tissue phantoms by means of CT Median CT density in the regions of interest (iron oxide deposits) was 450 HU (range: HU), whereas tissue specimens not containing iron had a median density of 55 HU. The injected iron mass in each tissue sample was 55.6 mg. The median detected iron mass in these samples by means of thin-sliced CT was 50 mg (range: mg), corresponding to 89.5% (range: 70 98%) Temperature measurements and thermal parameters An overview of nanoparticle imaging parameters, thermal data, and thermal doses for each patient is provided in Table 1. The temperatures were measured and calculated under constant magnetic field strengths between 4 and 5 ka/m, which were tolerated throughout the treatment time by all patients. Increasing magnetic field strength above these values in individual patients, significantly higher intraprostatic temperatures were recorded. For example, at 5 ka/m in the first patient, 48 8C was achieved in one probe. In patient 9, applying just above 5 ka/m yielded 55 8C in all four thermosensors. However, these field strengths were only tolerated for 5 10 min and these maximum temperatures were not decisive for the thermal dose determination. Higher magnetic field strengths caused burning sensations or dull pain in the groin or perineal region. In some patients, undesired temperature maxima of up to 44 8C were observed at the skin level, typically in folds of the scrotal and anal region. They could be readily alleviated by cooling and wiping off sweat from the skin. In all patients, the prostates were heatable 6 wk after magnetic fluid injection. The median decrease in T 90 from the first to the last heat session was 0.3 8C( 0.3 to 2.2). The median number of measurement points in the prostates/local recurrences during invasive thermometry was 28 (range: 11 35). The median T 20,T 50, and T 90 in the prostates were C (range; C), C (range: C), and C (range: C), respectively. Median urethral and rectal temperatures were C (range: C) and C (range: C). Only in patient 9, was the urinary catheter temporarily flushed with cool water. A correlation between urethral temperatures and calculations based on invasive intraprostatic temperature measurements revealed that mean intraluminally measured temperatures were 1.1 8C lower than calculated. The median calculated thermal dose derived from the fit of invasive and noninvasive measurements was CEM 43 8C T 90 = 7.8 min ( min; mean, 20.9 min). We found typical deviations between our direct (partially invasive) measurements and the (matched) simulated temperature distributions in specified regions: (1) Near to the floor of the bladder and in the urethra the direct temperature measurements tend to be below the calculations. This can be explained by a convection term not considered in the plan and by a thermal isolation effect of the catheter walls. (2) Towards the perineum (below the apex) the measurements tend to be above the calculations. This is probably due to a higher power deposition of the magnetic field in superficial regions. In the target area itself we found a satisfactory agreement between measurements and calculations, as illustrated in Fig Discussion

7 european urology 52 (2007) perature distribution during thermal therapies is indispensable to allow for thermal dosimetry, ensure effective treatment of the target region, and avoid damage of adjacent tissues [16]. The need for invasive thermometry and associated additional morbidity has always been a drawback regarding the acceptance of hyperthermia [17]. Great progress in the field of MRI-based thermometry has been made in recent years [18]. Although it hopefully may replace invasive temperature measurements in the future, the accuracy of noninvasive thermometry has not been evaluated in phase 3 studies. Furthermore, MRI is not suitable for thermotherapy using magnetic nanoparticles because of susceptibility artifacts, that is, imaging is disturbed by signal loss in the regions of interest [11]. A number of articles have focused on thermometry during hyperthermia of prostate cancer [19 23]. Particularly during interstitial hyperthermia of prostate cancer, high temperature heterogeneity was observed in this organ [19,20]. Even when extensive invasive thermometry was performed, invasive measurements seemed to provide an overestimation rather than an accurate picture of the three-dimensional temperature distribution in the prostate [19]. Thus, despite current shortcomings, imaging-based noninvasive temperature calculations have the potential to provide not only equivalent, but even more complete information compared to invasive measurements regarding temperature distribution during heat treatments [18]. To this end, thermal modelling simulations based on appropriate imaging techniques have been developed by several groups [21,22]. The models proposed for treatment planning and thermometry are closely connected to the heating devices used and therefore cannot be applied to other heating techniques. In the current study, we demonstrate that magnetic nanoparticle thermotherapy is feasible and that hyperthermic to thermoablative temperatures can be achieved in the prostates at relatively low magnetic field strengths. The power density of nanoparticle dispersions in a magnetic field, expressed by the SAR, may reach several thousands of watts per kilogram, depending on field strength, frequency, and the volume of distribution. With sufficiently high field strengths of ka/m, several hundreds of watts per kilogram could be achieved clinically using magnetic fluids, whereas values around 50 W/kg are typically achieved during regional hyperthermia [11,21,24]. In our current study, median SAR in the regions of the nanoparticles was 115 (90 170). By correlating CT-derived thermal data with direct temperature mappings in spatially defined measurement points, we established a method for noninvasive assessment of temperature using distributions of magnetic nanoparticles, which allowed us to estimate the threedimensional intraprostatic temperature distribution in each patient. Intraluminal measurements in the urethra consistently gave a lower temperature than expected from the invasive measurement data, probably due to thermal isolation exerted by the urethra and the walls of the catheter. Another reason is a convection remaining in the bladder catheter. In the interior of the prostate, however, we found a reasonable agreement of the planned temperature distribution with respect to the direct measurements. Further clinical validation of our noninvasive method of thermal analysis is warranted before invasive thermometry can be regarded as unnecessary. Our experimental data show that 89.5% of the injected amount of iron in tissue samples can be detected by CT, which allows for an analysis of treatment-related parameters with sufficient accuracy. It must be speculated that the remaining 10.5% represent areas with low concentration of iron, presumably in the periphery of larger depots or within the needle track. Contributions of very low concentrations of iron to the heating process of the whole target volume are physically negligible, so that their lack of detection would not significantly affect the thermal analysis based on CT data [2]. The dose concept of CEM 43 8CT 90 is based on the finding that high minimum temperatures achieved in most parts of the target volume correlate better with clinical outcome than maximum temperatures [25,26]. The mean CEM 43 8CT 90 of 20.9 min achieved in the current study compares favourably to the results of other groups using hyperthermia together with irradiation, who used the same definition of thermal dose, namely, Van Vulpen et al (interstitial hyperthermia: 0.47 min, external regional hyperthermia: 1.9 min), Anscher et al (external regional hyperthermia: 2.34 min), and Hurwitz et al (transrectal ultrasound hyperthermia: 8.4 min) [27 29]. Tilly et al found a CEM 6 min (in the urethra) in the group with prostate-specific antigen (PSA) control and 3 min in the PSA failure group [23]. The relatively high number of heat fractions in our study compensated for suboptimal heating in some patients and explains the satisfactory total thermal dose. It has been postulated that the minimum effective thermal dose for clinical studies using hyperthermia in conjunction with irradiation is a CEM 43 8C T 90 of 5 10 [23,30]. Adjuvant hyperthermia with a thermal dose >10 CEM 43 8C T 90 has been shown to correlate with

8 1660 european urology 52 (2007) improved tumour control when combined with radiation therapy in a phase 3 study on superficial tumours [14]. We conclude that the thermal dose achieved in our study using magnetic nanoparticles would be effective if combined with irradiation but not yet as a monotherapy. In the current study, alternating magnetic field strengths of 4 5 ka/m were tolerated throughout the treatment time. Because field strengths of up to 18 ka/m can be applied with the applicator used in this study and given the quadratic increase of SAR with increasing magnetic field strength, there is a tremendous potential for higher temperatures if higher H fields could be applied. The phenomenon of undesired heating outside the target region observed at skin folds can be explained by narrowing of the current path, leading to increases of current density and subsequent hot spots, especially when patients started sweating in the perineal region. Although this could be alleviated by additional cooling, technical improvements are necessary to allow for the safe application of higher magnetic field strengths. Such efforts are under way. Until magnetic nanoparticle thermotherapy is more refined and thermal ablation can be performed safely as a monotherapy, this treatment modality may be suitable for combination with irradiation in patients with localised prostate cancer. 5. Conclusions Interstitial heating using magnetic nanoparticles was feasible in patients with previously irradiated and locally recurrent prostate cancer. In principle, hyperthermic and thermoablative temperatures can be achieved in the prostates with this approach depending on the applied magnetic field strength. Homogeneous distribution of the nanoparticles in the prostates has not been achieved in this first study. A noninvasive thermometry method specific for magnetic nanoparticle thermotherapy was established and may serve as a tool for thermal dosimetry in future studies. Conflicts of interest Andreas Jordan is a manager and Uwe Gneveckow, Regina Scholz, and Norbert Waldöfner are employees at MagForce 1 Nanotechnologies AG, Berlin, Germany. The other authors declare that they do not have any affiliations that would lead to conflict of interest. Acknowledgement This study was supported by the EFRE Project NanoMed, Nanotechnology in Medicine, no ue/2 and in part by the Lieselotte-Beutel Foundation (project prostate center). The authors thank Lara Eckelt, Eva Wasserberg, Cornelia Cordes, Sabine Müller, Young-Suk Frisch, and Dipl. Ing. V. Brüß, for valuable technical assistance. References [1] Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 2002;43: [2] Jordan A, Maier-Hauff K, Wust P, Johannsen M. Nanoparticles for thermotherapy. In: Kumar CSSR, editor. Nanomaterials for cancer therapy. Weinheim: Wiley-VCH; p [3] Jordan A, Wust P, Fähling H, John W, Hinz A, Felix R. Inductive heating of ferrimagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia. Int J Hyperthermia 1993;9: [4] Jordan A, Wust P, Scholz R, et al. Effects of magnetic fluid hyperthermia (MFH) on C3H mammary carcinoma in vivo. Int J Hyperthermia 1997;13: [5] Jordan A, Scholz R, Maier-Hauff K, et al. The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol 2006;78:7 14. [6] Johannsen M, Jordan A, Scholz R, et al. Evaluation of magnetic fluid hyperthermia in a standard rat model of prostate cancer. J Endourol 2004;18: [7] Johannsen M, Thiesen B, Jordan A, et al. Magnetic fluid hyperthermia (MFH) reduces prostate cancer growth in the orthotopic Dunning R3327 rat model. Prostate 2005;64: [8] Johannsen M, Thiesen B, Gneveckow U, et al. Thermotherapy using magnetic nanoparticles combined with external radiation in an orthotopic rat model of prostate cancer. Prostate 2006;66: [9] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48: [10] Touma NJ, Izawa JI, Chin JL. Current status of local salvage therapies following radiation failure for prostate cancer. J Urol 2005;173: [11] Gneveckow U, Jordan A, Scholz R, et al. Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia. Med Phys 2004;31: [12] Johannsen M, Gneveckow U, Eckelt L, et al. Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique. Int J Hyperthermia 2005;21: [13] Sapareto SA, Dewey WC. Thermal dose determination in cancertherapy. Int J Radiat Oncol Biol Phys 1984;10: [14] Jones EL, Oleson JR, Prosnitz LR, et al. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 2005;23:

9 european urology 52 (2007) [15] Thrall DE, LaRue SM, Yu D, et al. Thermal dose is related to duration of local control in canine sarcomas treated with thermoradiotherapy. Clin Cancer Res 2005;11: [16] Jones E, Thrall D, Dewhirst MW, Vujaskovic Z. Prospective thermal dosimetry: the key to hyperthermia s future. Int J Hyperthermia 2006;22: [17] Van der Zee J, Peer-Valstar JN, Rietveld PJ, de Graaf-Strukowska I, van Rhoon C. Practical limitations of interstitial thermometry during deep hyperthermia. Int J Radiat Oncol Biol Phys 1998;40: [18] Wust P, Cho CH, Hildebrandt B, Gellermann J. Thermal monitoring: invasive, minimal-invasive and non-invasive approaches. Int J Hyperthermia 2006;22: [19] Van Vulpen M, Raaymakers BW, Lagendijk JJ, et al. Threedimensional controlled interstitial hyperthermia combined with radiotherapy for locally advanced prostate carcinoma a feasibility study. Int J Radiat Oncol Biol Phys 2002;53: [20] Van Vulpen M, De Leeuw AAC, Van de Kamer JB, et al. Comparison of intra-luminal versus intratumoral temperature measurements in patients with locally advanced prostate cancer treated with the coaxial TEM system: report of a feasibility study. Int J Hyperthermia 2003;19: [21] Tilly W, Wust P, Rau B, et al. Temperature data and specific absorption rates in pelvic tumours: predictive factors and correlations. Int J Hyperthermia 2001;17: [22] Raaymakers BW, Van Vulpen M, Lagendijk JJ, De Leeuw AAC, Crezee J, Battermann JJ. Determination and validation of the actual 3D temperature distribution during interstitial hyperthermia of prostate carcinoma. Phys Med Biol 2001;46: [23] Tilly W, Gellermann J, Graf R, et al. Regional hyperthermia in conjunction with definitive radiotherapy against recurrent or locally advanced prostate cancer T3 pn0 M0. Strahlenther Onkol 2005;181: [24] Wust P, Gneveckow U, Johannsen M, et al. Magnetic nanoparticles for interstitial thermotherapy feasibility, tolerance and achieved temperatures. Int J Hyperthermia 2006;22: [25] Dewhirst MW, Sim DA, Sapareto S, Connor WG. Importance of minimum tumor temperature in determining early and long term response of spontaneous canine and feline tumors to heat and radiation. Cancer Res 1984;44: [26] Thrall DE, Rosner GL, Azuma C, et al. Using units of CEM 43 8C T90, local hyperthermia thermal dose can be delivered as prescribed. Int J Hyperthermia 2000;16: [27] Van Vulpen M, De Leeuw AA, Raaymakers BW, et al. Radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate cancer: preliminary results. BJU Int 2004;93: [28] Anscher MS, Samulski TV, Dodge R, Prosnitz LR, Dewhirst MW. Combined external beam irradiation and external regional hyperthermia for locally advanced adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1997;37: [29] Hurwitz MD, Kaplan ID, Hansen JL, et al. Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile. Int J Hyperthermia 2005;21: [30] Oleson JR, Samulski TV, Leopold KA, et al. Sensitivity of hyperthermia trial outcomes to temperature and time: Implications for thermal goals of treatment. Int J Radiat Oncol Biol Phys 1993;25: Editorial Comment Mark Hurwitz, Department of Radiation Oncology, Dana-Farber/Brigham & Women s Cancer Center, Harvard Medical School, Boston, MA, USA mhurwitz@lroc.harvard.edu Johannsen et al here report the initial technical results using a novel technique for administration of hyperthermia for prostate cancer. Use of magnetic nanoparticles and thermal modeling based on the bio-heat transfer equation are the manifestation of innovative thinking welcome in the field of thermal therapy. Challenges in both administration and monitoring hyperthermia, however, are not trivial as the findings of this early stage trial well demonstrate. Although the authors convincingly suggest that higher temperatures can yet be achieved, questions remain as to how well nanoparticles can be distributed, particularly in a previously irradiated prostate. This is a key concern in terms of optimizing heat distribution to cancerous tissue while limiting toxicity. Estimation and quantification of temperature are other challenges for hyperthermia, where as opposed to radiation, not only physics but physiology must be accounted for in defining thermal dose. The authors use of the bio-heat transfer equation to model thermal dose thereby replacing thermal monitoring is an intriguing concept. Whereas correlative spatial temperature trends were demonstrated, differences in modeled versus actual temperature measurements that at times were several degrees Celsius lead one to conclude we are not yet capable of relying on modeling as opposed to monitoring. Efforts to improve modeling, which may come in tandem with more complete understanding of spatial and temporal temperature distributions possible with noninvasive thermal monitoring, should nevertheless be encouraged. An ever-increasing array of techniques is available for hyperthermia, none more so than for

10 1662 european urology 52 (2007) prostate cancer given the relative ease of external, interstitial, or transrectal heat application. It is doubtful that any one technique will ultimately prove superior to all others. Through participation in the process of developing one among perhaps several winning techniques, the authors thoughtful efforts bring us closer to a more important goal of ensuring that our patients are the ultimate winners as we strive to optimize thermal therapy.