John G. Wolbers

Tissue uptake of BSH in patients with glioblastoma in the EORTC 11961 phase I BNCT trial.

Purpose: The uptake of the boron compound Na2B12H10-SH (BSH) in tumor and normal tissues was investigated in the frame of the EORTC phase I trial ‘Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility’ (protocol 11961).Methods and Materials: The boron concentration in blood, tumor, normal brain, dura, muscle, skin and bone was detected using inductively coupled plasma-atomic emission spectroscopy in 13 evaluable patients. In a first group of 10 patients 100 mg BSH/kg bodyweight (BW) were administered; a second group of 3 patients received 22.9 mg BSH/kg BW. The toxicity due to BSH was evaluated.Results: The average boron concentration in the tumor was 19.9±9.1 ppm (1 standard deviation (SD)) in the high dose group and 9.8±3.3 ppm in the low dose group, the tumor/blood ratios were 0.6±0.2 and 0.9±0.2, respectively. The highest boron uptake has been detected in the dura, very low uptake was found in the bone, the cerebro-spinal fluid and especially in the brain (brain/blood ratio 0.2±0.02 and 0.4±0.2). No toxicity was detected except flush-like symptoms in 2 cases during a BSH infusion at a much higher speed than prescribed.Conclusion: BSH proved to be safe for clinical application at a dose of 100 mg BSH/kg infused and at a dose rate of 1 mg/kg/min. The study underlines the importance of a further investigation of BSH uptake in order to obtain enough data for significant statistical analysis. The boron concentration in blood seems to be a quite reliable parameter to predict the boron concentration in other tissues.

Organisation and management of the first clinical trial of BNCT in Europe (EORTC Protocol 11961)

Boron Neutron Capture Therapy is based on the ability of the isotope10B to capture thermal neutrons and to disintegrate instantaneously producing high LET particles. The only neutron beam available in Europe for such a treatment is based at the European High Flux Reactor HFR at Petten (The Netherlands). The European Commission, owners of the reactor, decided that the potential benefit of the facility should be opened to all European citizens and therfore insisted on a multinational approach to perform the first clinical trial in Europe on BNCT. This precondition had to be respected as well as the national laws and regulations. Together with the Dutch authorities actions were undertaken to overcome the obvious legal problems. Furthermore, the clinical trial at Petten takes place in a nuclear research reactor, which apart from being conducted in a non-hospital environment, is per se known to be dangerous. It was therefore of the utmost importance that special attention is given to safety, beyond normal rules, and to the training of staff. In itself, the trial is an unusual Phase I study, introducing a new drug with a new irradiation modality, with really an unknown dose-effect relationship. This trial must follow optimal procedures, which underscore the quality and qualified manner of performance.

Additive cytotoxic effect of cisplatin and X-irradiation on human glioma cell cultures derived from biopsy-tissue

Purpose: Investigation of the in vitro cytotoxic effect of X-rays, either alone or combined with cisplatin on early passage cell cultures derived from human glioblastoma multiforme biopsy tissue. Materials and methods: Fresh tumour specimens from four patients were processed to cell cultures. The U373 glioma cell line was used as a reference. Early passage cell cultures were X-irradiated (0–8 Gy) either alone or in combination with cisplatin (0.5–1 μg/ml). Cell survival was determined by either clonogenic assay or the colorimetric MTT assay. Survival curves were generated and mathematically analysed using the linear quadratic model, to obtain the radiosensitivity parameters α, β, and SF2, i.e., the Surviving Fraction after 2 Gy. Results: Two patient-derived glioma cell cultures and the U373 cell line showed rather high SF2 values of 0.61–0.72 in the clonogenic assay, indicating relative high radiation resistance. Cisplatin alone (1 μg/ml) reduced cell survival by 10–30% (n=4). When combined with irradiation, a clear additive cytotoxic effect of cisplatin was demonstrated by the unaltered value of the α-parameter for reproductive cell death. Conclusion: Cisplatin exerted an additive rather than radiosensitising cytotoxic effect in uncharacterised patient derived glioma cell cultures.

Thallium-201 SPECT as response parameter for PCV chemotherapy in recurrent glioma.

Combination chemotherapy with procarbazine, CCNU and vincristine (PCV) may be effective in patients with recurrent glioma. Response monitoring is mandatory, but radiological response evaluation is often difficult. We evaluated Thallium-201 (201Tl) SPECT as a response parameter in ten patients treated with intensive PCV chemotherapy for recurrent glioma. 201Tl-SPECT studies showed early changes (decreasing volume and intensity) in nine patients and these changes were more pronounced than radiological findings. 201Tl-SPECT results after completion of chemotherapy seemed to correlate with clininal findings during follow up. We conclude that 201Tl-SPECT may contribute to the assessment of response in patients treated with PCV chemotherapy for recurrent glioma.

Methotrexate induced brain necrosis and severe leukoencephalopathy due to disconnection of an Ommaya device

SummaryA 63-year old woman with breast carcinoma developed leucoencephalopathy and local brain necrosis after intraparenchymal infusion of methotrexate. This iatrogenic condition was caused by drain disconnection of the Ommaya device (bore hole type). The diagnosis of this rare complication of an Ommaya device was based on multiplanar MR-imaging. The case is discussed with regard to the complications of intraventricular chemotherapy by means of an Ommaya reservoir.

Report on the First Patient Group of the European Phase I Trial (EORTC Protocol 11961) at the High Flux Reactor Petten

The first European clinical trial on BNCT (EORTC protocol 11961) started in 1997.1 Thjs is a phase I study, aimed to define the Maximum Tolerated Dose and Dose Limiting Toxicity in gliobastoma patients using BSH as boron carrier and fractionated radiation at the Epithermal Neutron Facility at Petten. Beside the evaluation of the systemic toxicity of BSH, and the early radiation toxicity in the irradiated volume, special emphasis has been placed on the late radiation morbidity. In addition survival will be observed. Up to this date 14 patients have been entered into the study, 12 males and 2 females at six Neurosurgery Centers in five European countries.

Status Report on the European Clinical Trial of BNCT at Petten (EORTC Protocol 11961)

In October 1997, after a preparatory phase of 8 years, the first patient in Europe was treated by BNCT at the High Flux Reactor (HFR) of the European Commission in Petten, The Netherlands.1 The preparation for the first clinical BNCT trial in Europe included comprehensive scientific experimental and human investigations with the boron compound borocaptate sodium (BSH).2,3 A multitude of open legal and administrative questions had to be overcome. Furthermore a complex structure had to be organized and the procedures had to be defined how to perform a multi-national, multi-institutional study using a nuclear reactor distant from hospital for patient treatment performed by an international team on a multidisciplinary base.4 The international standards of clinical research as well as the accepted rules and definitions of conventional radiotherapy were applied, involving independent experts in order to assure the quality of the study and the quality of the Performance of patient treatment. The goal was to execute the project to a very high Standard as would be expected in the leading radiotherapy depart-ments in Europe.5

QUALITY MANAGEMENT AT THE EUROPEAN BNCT CENTER IN PETTEN

Boron Neutron Capture Therapy is based on the ability of the isotope 10B to capture thermal neutrons and to disintegrate instantaneously producing the high LET particles, He and Li nuclei, with a high kinetic energy of about 2.5 MeV and a very short range in tissue of about 10μm [10B(n,α)7Li]. If such reactions can be produced selectively in tumour cells, an effective new modality for cancer treatment would be available. In the 1950’s and early 1960’s, BNCT trials in the USA were effectively a failure.1 Nevertheless, in the late 60’s, Hatanaka in Japan demonstrated that BNCT does benefit patients.2 However, the reported results were difficult to interpret, because the treatment was not carried out in a controlled manner. In 1994, new trials started in the USA (at Brookhaven National Laboratory BNL3 and Massachusetts Institute of Technology MIT4) involving glioblastoma (at BNL and MIT) and melanoma (at MIT). Meanwhile in Europe in the late 1980’s, effective research into introducing BNCT began following the injection of financial support from the Biomedicine and Health Research programme (BIOMED I) of the European Commission. This has lead recently to the start of clinical trials of BNCT for glioblastoma multiforme, with the aim to establish a safe radiation dose for the treatment of brain tumours.5 It is the first time that a clinical application has had to be realised on a real multi-national scale, whereby a unique facility available for BNCT is localised in one country (The Netherlands) and is operated by an international team of experts under the leadership of a German radiotherapist, treating patients coming from different European countries. It was therefore necessary that special structures had to be created with the support of administrations from different countries, who had to find and adapt solutions within existing laws that had never foreseen such a situation.

Psychological Aspects of the Patient Treatment by BNCT at Petten

The conduction of a phase I trial especially with incurable cancer involves a psychological burden for both sides: the patients and the staff as well. In addition the trial in progress is a multi-disciplinary, multi-national, multi-institutional study, outside of the traditional medical structure. The effectiveness of the team functioning is variable ranging from productive interdisciplinary collaboration to fragmented service coordination loaded with high emotional costs, tension, conflicts and frustrations. On the other hand due to the particular circumstances at Petten5, 6 both the BNCT-team members and the patients can gain paramount psychological benefit from the new emerging interdisciplinary field that use techniques from previous separate scientific disciplines. It considers key organisational, professional and interpersonal challenges that need to be analysed in order to address the possible ways of improvement if the present level of teamwork is to be enhanced or strengthen the present available advantages.1

The Pharmacokinetics of BSH Following Single and Multiple Administrations

In EORTC trial 11961 “Glioma Treatment with BNCT”, the treatment with BNCT is given in four fractions, on four consecutive days. Prior to each fraction, BSH (Na2B12H11SH) is infused in amounts such that 30ppm boron is reached as average over the four fractions. Before the BNCT treatment, BSH is administered at the time point of surgery, in order to gain data on the pharmacokinetics of BSH in the individual patient. On this basis, and assuming that each dosage of BSH is purely additive and that the pharmacokinetics of BSH at surgery is a good prediction of the pharmacokinetics at treat-ment, an individual prescription scheme can be established beforehand.