Uwe Gneveckow

Clinical hyperthermia of prostate cancer using magnetic nanoparticles: Presentation of a new interstitial technique

The aim of this pilot study was to evaluate whether the technique of magnetic fluid hyperthermia can be used for minimally invasive treatment of prostate cancer. This paper presents the first clinical application of interstitial hyperthermia using magnetic nanoparticles in locally recurrent prostate cancer. Treatment planning was carried out using computerized tomography (CT) of the prostate. Based on the individual anatomy of the prostate and the estimated specific absorption rate (SAR) of magnetic fluids in prostatic tissue, the number and position of magnetic fluid depots required for sufficient heat deposition was calculated while rectum and urethra were spared. Nanoparticle suspensions were injected transperineally into the prostate under transrectal ultrasound and flouroscopy guidance. Treatments were delivered in the first magnetic field applicator for use in humans, using an alternating current magnetic field with a frequency of 100 kHz and variable field strength (0–18 kA m−1). Invasive thermometry of the prostate was carried out in the first and last of six weekly hyperthermia sessions of 60 min duration. CT-scans of the prostate were repeated following the first and last hyperthermia treatment to document magnetic nanoparticle distribution and the position of the thermometry probes in the prostate. Nanoparticles were retained in the prostate during the treatment interval of 6 weeks. Using appropriate software (AMIRA), a non-invasive estimation of temperature values in the prostate, based on intra-tumoural distribution of magnetic nanoparticles, can be performed and correlated with invasively measured intra-prostatic temperatures. Using a specially designed cooling device, treatment was well tolerated without anaesthesia. In the first patient treated, maximum and minimum intra-prostatic temperatures measured at a field strength of 4.0–5.0 kA m−1 were 48.5°C and 40.0°C during the 1st treatment and 42.5°C and 39.4°C during the 6th treatment, respectively. These first clinical experiences prompted us to initiate a phase I study to evaluate feasibility, toxicity and quality of life during hyperthermia using magnetic nanoparticles in patients with biopsy-proven local recurrence of prostate cancer following radiotherapy with curative intent. To the authors’ knowledge, this is the first report on clinical application of interstitial hyperthermia using magnetic nanoparticles in the treatment of human cancer.

Morbidity and quality of life during thermotherapy using magnetic nanoparticles in locally recurrent prostate cancer: Results of a prospective phase I trial

Purpose: To investigate the treatment-related morbidity and quality of life (QoL) during thermotherapy using superparamagnetic nanoparticles in patients with locally recurrent prostate cancer. Materials and Methods: Ten patients with biopsy-proven locally recurrent prostate cancer following primary therapy with curative intent and no detectable metastases were entered on a prospective phase I trial. Endpoints were feasibility, toxicity and QoL. Following intraprostatic injection of a nanoparticle dispersion, six thermal therapy sessions of 60 min duration were delivered at weekly intervals using an alternating magnetic field. National Cancer Institute (NCI) common toxicity criteria (CTC) and the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-PR25 questionnaires were used to evaluate toxicity and QoL, respectively. In addition, prostate specific antigen (PSA) measurements were carried out. Results: Maximum temperatures up to 55°C were achieved in the prostates at 25–30% of the available magnetic field strength. Nanoparticle deposits were detectable in the prostates one year after thermal therapy. At a median follow-up of 17.5 months (3–24), no systemic toxicity was observed. Acute urinary retention occurred in four patients with previous history of urethral stricture. Treatment-related morbidity was moderate and QoL was only temporarily impaired. Prostate-specific antigen (PSA) declines were observed in eight patients. Conclusions: Interstitial heating using magnetic nanoparticles was feasible and well tolerated in patients with locally recurrent prostate cancer. Deposition of nanoparticles in the prostate was highly durable. Further refinement of the technique is necessary to allow application of higher magnetic field strengths.

Post-mortem studies in glioblastoma patients treated with thermotherapy using magnetic nanoparticles

Patients with glioblastoma multiforme (GBM), the most common primary brain tumor in adults, have still a poor prognosis though new strategies of radio- and chemotherapy have been developed. Recently, our group demonstrated the feasibility, tolerability and anti-tumoral effects of a newly developed therapeutic approach, termed thermotherapy using magnetic nanoparticles or magnetic fluid hyperthermia (MFH), in a murine model of malignant glioma. Currently, the efficacy of MFH is being evaluated in a phase II study. Here, we report on post-mortem neuropathological findings of patients with GBM receiving MFH. In brain autopsies the installed magnetic nanoparticles were dispersed or distributed as aggregates within geographic tumor necroses, restricted in distribution to the sites of instillation. Therefore, our results underscore the need for multiple trajectories of instillation. The typical GBM necrosis with pseudopalisading was free of particles. Dispersed particles and particle aggregates were phagocytosed mainly by macrophages whereas glioblastoma cells showed an uptake to a minor extent. MFH therapy further promotes uptake of nanoparticles in macrophages, likely as a consequence of tumor inherent and therapy induced formation of necrosis with subsequent infiltration and activation of phagocytes. We did not observe bystander effects of MFH such as sarcomatous tumour formation, formation of a sterile abscess or foreign body giant cell reaction. Furthermore, all patients did not present any clinical symptoms related to possible adverse effects of MFH.

Magnetic nanoparticles for interstitial thermotherapy - : feasibility, tolerance and achieved temperatures

Background: The concept of magnetic fluid hyperthermia is clinically evaluated after development of the whole body magnetic field applicator MFH® 300F and the magnetofluid MFL 082AS. This new system for localized thermotherapy is suitable either for hyperthermia or thermoablation. The magnetic fluid, composed of iron oxide nanoparticles dispersed in water, must be distributed in the tumour and is subsequently heated by exposing to an alternating magnetic field in the applicator. We performed a feasibility study with 22 patients suffering from heavily pretreated recurrences of different tumour entities, where hyperthermia in conjunction with irradiation and/or chemotherapy was an option. The potential to estimate (by post-implantation analyses) and to achieve (by improving the technique) a satisfactory temperature distribution was evaluated in dependency on the implantation technique. Material and methods: Three implantation methods were established: Infiltration under CT fluoroscopy (group A), TRUS (transrectal ultrasound) – guided implantation with X-fluoroscopy (group B) and intra-operative infiltration under visual control (group C). In group A and B the distribution of the nanoparticles can be planned prior to implantation on the basis of three-dimensional image datasets. The specific absorption rates (SAR in W/kg) can be derived from the particle distribution imaged via CT together with the actual H-field strength (in kA/m). The temperature distribution in the tumour region is calculated using the bioheat-transfer equation assessing a mean perfusion value, which is determined by matching calculated temperatures to direct (invasive or endoluminal) temperature measurements in reference points in or near the target region. Results: Instillation of the magnetic fluid and the thermotherapy treatments were tolerated without or with only moderate side effects, respectively. Using tolerable H-field-strengths of 3.0–6.0 kA/m in the pelvis, up to 7.5 kA/m in the thoracic and neck region and >10.0 kA/m for the head, we achieved SAR of 60–380 W/kg in the target leading to a 40°C heat-coverage of 86%. However, the coverage with ≥42°C is unsatisfactory at present (30% of the target volume in group A and only 0.2% in group B). Conclusion: Further improvement of the temperature distribution is required by refining the implantation techniques or simply by increasing the amount of nanofluid or elevation of the magnetic field strength. From the actual nanoparticle distribution and derived temperatures we can extrapolate, that already a moderate increase of the H-field by only 2 kA/m would significantly improve the 42°C coverage towards 100% (98%). This illustrates the great potential of the nanofluid-based heating technology.

Description and characterization of the novel hyperthermia- and thermoablation-system MFH 300F for clinical magnetic fluid hyperthermia.

Magnetic fluid hyperthermia (MFH) is a new approach to deposit heat power in deep tissues by overcoming limitations of conventional heat treatments. After infiltration of the target tissue with nanosized magnetic particles, the power of an alternating magnetic field is transformed into heat. The combination of the 100 kHz magnetic field applicator MFH 300F and the magnetofluid (MF), which both are designed for medical use, is investigated with respect to its dosage recommendations and clinical applicability. We found a magnetic field strength of up to 18 kA/m in a cylindrical treatment area of 20 cm diameter and aperture height up to 300 mm. The specific absorption rate (SAR) can be controlled directly by the magnetic field strength during the treatment. The relationship between magnetic field strength and the iron normalized SAR (SAR(Fe)) is only slightly depending on the concentration of the MF and can be used for planning the target SAR. The achievable energy absorption rates of the MF distributed in the tissue is sufficient for either hyperthermia or thermoablation. The fluid has a visible contrast in therapeutic concentrations on a CT scanner and can be detected down to 0.01 g/l Fe in the MRI. The system has proved its capability and practicability for heat treatment in deep regions of the human body.

18F-FET PET for planning of thermotherapy using magnetic nanoparticles in recurrent glioblastoma

Purpose: Thermotherapy using magnetic nanoparticles (nano cancer therapy) is a new concept of local tumour therapy, which is based on controlled heating of intra-tumoural injected magnetic nanoparticles. The aim of this study was to evaluate the usefulness of PET with a recently introduced amino acid tracer O-(2-[18F]fluoroethyl)-]L-tyrosine (FET) for targeting the nanoparticles implantation. Materials and methods: Eleven patients with glioblastoma recurrences underwent MR and FET-PET imaging for planning of the nano cancer therapy. Thereafter, the gross tumour volumes (GTV) were defined, taking into consideration the results of both imaging tools. Results: The MRI-based mean GTV was 24.3 cm3 (range 2.5–59.7) and the PET-based mean GTV 31.9 cm3 (range 5.2–77.9). On the average the MRI identified an additional 8.9 ± 4.7 cm3 and the FET-PET scan—an additional 16.5 ± 15.2 cm3 outside of the common GTV (15.4 ± 11.0 cm3). The mean final GTV accounted to 33.8 cm3 (range, 5.2–77.9). The additional information of FET-PET led to an increase in GTV by 22–286% in eight patients and to a decrease of 23% and 26%, respectively, in two patients. In one patient, the final GTV was defined on the basis of MRI data only. Conclusions: FET-PET adds important information on the actual tumour volume in recurrent glioblastomas and is highly valuable for defining the target volume for the nano cancer therapy.

Termoterapia en cáncer de próstata mediante el uso de nanopartículas magnéticas

A novel method of interstitial heating using magnetic nanoparticles and a direct injection technique has been evaluated in human cancers in recent clinical trials. In prostate cancer, this approach was investigated in two separate phase-I-studies, employing magnetic nanoparticle thermotherapy alone and in combination with permanent seed brachytherapy. The feasibility and good tolerability was shown in both trials, using the first prototype of a magnetic field applicator. As with any other heating technique, this novel approach requires specific tools for planning, quality control and thermal monitoring, based on appropriate imaging and modelling techniques. In these first clinical trials, a newly developed method for planning and non-invasive calculations of the 3-dimensional temperature distribution based on computed tomography could be validated. Limiting factors of this approach at present are patient discomfort at high magnetic field strengths and suboptimal intratumoral distribution of nanoparticles. Until these limitations will be overcome and thermal ablation can safely be applied as a monotherapy, this treatment modality is being evaluated in combination with irradiation in patients with localized prostate cancer.