Elsevier

European Urology

Volume 52, Issue 6, December 2007, Pages 1653-1662
European Urology

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

https://doi.org/10.1016/j.eururo.2006.11.023Get rights and content

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 °C were achieved in the prostates. Median temperatures in 20%, 50%, and 90% of the prostates were 41.1 °C (range: 40.0–47.4 °C), 40.8 °C (range: 39.5–45.4 °C), and 40.1 °C (range: 38.8–43.4 °C), respectively. Median urethral and rectal temperatures were 40.5 °C (range: 38.4–43.6 °C) and 39.8 °C (range: 38.2–43.4 °C). The median thermal dose was 7.8 (range: 3.5–136.4) cumulative equivalent minutes at 43 °C 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.

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.

References (30)

  • A. Jordan et al.

    Effects of magnetic fluid hyperthermia (MFH) on C3H mammary carcinoma in vivo

    Int J Hyperthermia

    (1997)
  • A. Jordan et al.

    The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma

    J Neurooncol

    (2006)
  • M. Johannsen et al.

    Evaluation of magnetic fluid hyperthermia in a standard rat model of prostate cancer

    J Endourol

    (2004)
  • M. Johannsen et al.

    Magnetic fluid hyperthermia (MFH) reduces prostate cancer growth in the orthotopic Dunning R3327 rat model

    Prostate

    (2005)
  • M. Johannsen et al.

    Thermotherapy using magnetic nanoparticles combined with external radiation in an orthotopic rat model of prostate cancer

    Prostate

    (2006)
  • Cited by (454)

    • Neurosurgical Applications of Magnetic Hyperthermia Therapy

      2023, Neurosurgery Clinics of North America
    View all citing articles on Scopus
    1

    M.J. and U.G. contributed equally to this manuscript.

    View full text