EORTC trial 11001: distribution of two 10B-compounds in patients with squamous cell carcinoma of head and neck, a translational research/phase 1 trial.

Boron neutron capture therapy (BNCT) provides highly targeted delivery of radiation through the limited spatial distribution of its effects. This translational research/phase I clinical trial investigates whether BNCT might be developed as a treatment option for squamous cell carcinoma of head and neck (SCCHN) relying upon preferential uptake of the two compounds, sodium mercaptoundecahydro-closo-dodecaborate (BSH) or L-para-boronophenylalanine (BPA) in the tumour. Before planned tumour resection, three patients received BSH and three patients received BPA. The (10)B-concentration in tissues and blood was measured with prompt gamma ray spectroscopy. Adverse effects from compounds did not occur. After BPA infusion the (10)B-concentration ratio of tumour/blood was 4.0 +/- 1.7. (10)B-concentration ratios of tumour/normal tissue were 1.3 +/- 0.5 for skin, 2.1 +/- 1.2 for muscle and 1.4 +/- 0.01 for mucosa. After BSH infusion the (10)B-concentration ratio of tumour/blood was 1.2 +/- 0.4. (10)B-concentration ratios of tumour/normal tissue were 3.6 +/- 0.6 for muscle, 2.5 +/- 1.0 for lymph nodes, 1.4 +/- 0.5 for skin and 1.0 +/- 0.3 for mucosa. BPA and BSH deliver (10)B to SCCHN to an extent that might allow effective BNCT treatment. Mucosa and skin are the most relevant organs at risk.

Laser postionization secondary neutral mass spectrometry in tissue: a powerful tool for elemental and molecular imaging in the development of targeted drugs.

The exact intracellular localization and distribution of molecules and elements becomes increasingly important for the development of targeted therapies and contrast agents. We show that laser postionization secondary neutral mass spectrometry (laser-SNMS) is well suited to localize particular elements and small molecules with subcellular spatial resolution applying the technique exemplary to Boron Neutron Capture Therapy (BNCT). We showed in a murine sarcoma that the drugs used for clinical BNCT, namely l-para-boronophenylalanine (700 mg/kg body weight i.p.) and sodium mercaptoundecahydro-closo-dodecaborate (200 mg/kg body weight i.p.), transport the therapeutic agent (10)B into the cytoplasm and into the nucleus itself, the most sensitive area of the cell. Sodium mercaptoundecahydro-closo-dodecaborate distributes (10)B homogeneously and l-para-boronophenylalanine heterogeneously. When combining laser-SNMS with prompt gamma-ray analysis as a screening technique, strategies for BNCT can be elaborated to develop new drugs or to improve the use of existing drugs on scientifically based evidence. The study shows the power of laser-SNMS in the early stages of drug development, also outside BNCT.

Neutron activation of patients following boron neutron capture therapy of brain tumors at the high flux reactor (HFR) Petten (EORTC Trials 11961 and 11011).

BACKGROUND AND PURPOSE: At the High Flux Reactor (HFR), Petten, The Netherlands, EORTC clinical trials of Boron Neutron Capture Therapy (BNCT) have been in progress since 1997. BNCT involves the irradiation of cancer patients by a beam of neutrons, with an energy range of predominantly 1 eV to 10 keV. The patient is infused with a tumor-seeking, (10)B-loaded compound prior to irradiation. Neutron capture in the (10)B atoms results in a high local radiation dose to the tumor cells, whilst sparing the healthy tissue. Neutron capture, however, also occurs in other atoms naturally present in tissue, sometimes resulting in radionuclides that will be present after treatment. The patient is therefore, following BNCT, radioactive. The importance of this induced activity with respect to the absorbed dose in the patient as well as to the radiation exposure of the staff has been investigated. MATERIAL AND METHODS: As a standard radiation protection procedure, the ambient dose equivalent rate was measured on all patients following BNCT using a dose ratemeter. Furthermore, some of the patients underwent measurements using a gamma-ray spectrometer to identify which elements and confirm which isotopes are activated. RESULTS: Peak levels, i.e., at contact and directly after irradiation, are of the order of 40-60 muSv/h, falling to < 10 muSv/h 30-50 min after treatment. The average ambient dose equivalent in the first 2 h at a distance of 2 m from the patient is in the order of 2.5 muSv. The ambient dose equivalent rate in 2 m distance from the patient's head at the earliest time of leaving the reactor center (20 min after the end of treatment) is far less than 1 muSv/h. The main radioisotopes were identified as (38)Cl, (49)Ca, and (24)Na. Furthermore, in two patients, the isotopes (198)Au and (116m)In were also present. The initial activity is predominantly due to (49)Ca, whilst the remaining activity is predominantly due to (24)Na. CONCLUSION: The absorbed dose resulting from the activated isotopes in the irradiated volume is in the order of < 1% of the prescribed dose and therefore does not add a significant contribution to the absorbed dose in the target volume. In other parts of the patient's body, the absorbed dose by induced activity is magnitudes smaller and can be neglected. The levels of radiation received by staff members and non-radiation workers (i.e., accompanying persons) are well below the recommended limits.