Prostate CancerThermotherapy of Prostate Cancer Using Magnetic Nanoparticles: Feasibility, Imaging, and Three-Dimensional Temperature Distribution
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], [5], [6], [7], [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.
Section snippets
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
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
Discussion
Temperatures between 40 °C and 45 °C are generally being referred to as hyperthermia. Temperatures of up to 42 °C can render cancer cells more susceptible to the effects of irradiation and cause a certain degree of apoptosis, whereas temperatures >45 °C are termed thermoablation and cause direct cell killing [1]. Knowledge of the intratumoural temperature distribution during thermal therapies is indispensable to allow for thermal dosimetry, ensure effective treatment of the target region, and avoid
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
Conflicts of interest
Andreas Jordan is a manager and Uwe Gneveckow, Regina Scholz, and Norbert Waldöfner are employees at MagForce® 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. 2000-22006 2ue/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.
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M.J. and U.G. contributed equally to this manuscript.