Paving the Road for Modern Particle Therapy - What Can We Learn from the Experience Gained with Fast Neutron Therapy in Munich?

While neutron therapy was a highly topical subject in the 70s and 80s, today there are only a few remaining facilities offering fast neutron therapy (FNT). Nevertheless, up to today more than 30,000 patients were treated with neutron therapy. For some indications like salivary gland tumors and malignant melanoma, there is clinical evidence that the addition of FNT leads to superior local control compared to photon treatment alone. FNT was available in Munich from 1985 until 2000 at the Reactor Neutron Therapy (RENT) facility. Patient treatment continued at the new research reactor FRM II in 2007 under improved treatment conditions, and today it can still be offered to selected patients as an individual treatment option. As there is a growing interest in high-linear energy transfer (LET) therapy with new hadron therapy centers emerging around the globe, the clinical data generated by neutron therapy might help to develop biologically driven treatment planning algorithms. Also FNT might experience its resurgence as a combinational partner of modern immunotherapies.

Boron containing magnetic nanoparticles for neutron capture therapy--an innovative approach for specifically targeting tumors.

The selective delivery of (10)B into the tumor tissue remains to be further improved for successful and reliable Boron Neutron Capture Therapy applications. Magnetic Drug Targeting using intraarterially administered superparamagnetic nanoparticles and external magnetic fields already exhibited convincing results in terms of highly efficient and selective drug deposition. Using the same technique for the targeted (10)B delivery is a promising new approach. Here, systematic irradiation experiments of phantom cubes containing different concentrations of boron and nanoparticles as well as varying three-dimensional arrangements have been performed.

Hemorrhage in mouse tumors induced by dodecaborate cluster lipids intended for boron neutron capture therapy.

The potential of boron-containing lipids with three different structures, which were intended for use in boron neutron capture therapy, was investigated. All three types of boron lipids contained the anionic dodecaborate cluster as the headgroup. Their effects on two different tumor models in mice following intravenous injection were tested; for this, liposomes with boron lipid, distearoyl phosphatidylcholine, and cholesterol as helper lipids, and containing a polyethylene glycol lipid for steric protection, were administered intravenously into tumor-bearing mice (C3H mice for SCCVII squamous cell carcinoma and BALB/c mice for CT26/WT colon carcinoma). With the exception of one lipid (B-THF-14), the lipids were well tolerated, and no other animal was lost due to systemic toxicity. The lipid which led to death was not found to be much more toxic in cell culture than the other boron lipids. All of the lipids that were well tolerated showed hemorrhage in both tumor models within a few hours after administration. The hemorrhage could be seen by in vivo magnetic resonance and histology, and was found to occur within a few hours. The degree of hemorrhage depended on the amount of boron administered and on the tumor model. The observed unwanted effect of the lipids precludes their use in boron neutron capture therapy.

Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer.

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 µg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or "BPA", and sodium borocaptate or "BSH" (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.

First steps towards a fast-neutron therapy planning program.

BACKGROUND: The Monte Carlo code GEANT4 was used to implement first steps towards a treatment planning program for fast-neutron therapy at the FRM II research reactor in Garching, Germany. Depth dose curves were calculated inside a water phantom using measured primary neutron and simulated primary photon spectra and compared with depth dose curves measured earlier. The calculations were performed with GEANT4 in two different ways, simulating a simple box geometry and splitting this box into millions of small voxels (this was done to validate the voxelisation procedure that was also used to voxelise the human body). RESULTS: In both cases, the dose distributions were very similar to those measured in the water phantom, up to a depth of 30 cm. In order to model the situation of patients treated at the FRM II MEDAPP therapy beamline for salivary gland tumors, a human voxel phantom was implemented in GEANT4 and irradiated with the implemented MEDAPP neutron and photon spectra. The 3D dose distribution calculated inside the head of the phantom was similar to the depth dose curves in the water phantom, with some differences that are explained by differences in elementary composition. The lateral dose distribution was studied at various depths. The calculated cumulative dose volume histograms for the voxel phantom show the exposure of organs at risk surrounding the tumor. CONCLUSIONS: In order to minimize the dose to healthy tissue, a conformal treatment is necessary. This can only be accomplished with the help of an advanced treatment planning system like the one developed here. Although all calculations were done for absorbed dose only, any biological dose weighting can be implemented easily, to take into account the increased radiobiological effectiveness of neutrons compared to photons.

The Munich Fission Neutron Therapy Facility MEDAPP at the research reactor FRM II.

PURPOSE: At the new research reactor FRM II of the Technical University of Munich (TUM), the facility for Medical Applications (MEDAPP) was installed where fast neutrons are available as a beam for medical use. MATERIAL AND METHODS: Thermal neutrons induce fission in a pair of uranium converter plates and generate fast neutrons which are guided to the patient by a beam tube. The maximum opening of the multi leaf collimator (MLC) is 30x20 cm2 WxH. The beam is characterized by neutron-photon mixed beam phantom dosimetry. Specific safety measures are outlined. RESULTS: The neutron and gamma dose rates are 0.52 Gy/min and 0.20 Gy/min, respectively, in 2 cm depth of a water phantom. The half maximum depth of the neutron dose rate in water is 5.4 cm (mean neutron energy 1.9+/-0.1 MeV). Conformity with the European Medical Devices Directive (MDD) 93/42/EEG, was proven so that MEDAPP has a CE mark and since February 2007 also the license for clinical operation. CONCLUSION: The clinical neutron irradiations of malignant tumors, which were performed at the former research reactor FRM until 2000, can be continued at FRM II under improved conditions. First patients were irradiated in June 2007.