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Catching neutrons to combat cancer

High-flux reactor (HFR) of the JRC Institute for Advanced Materials.
Four groups of 10 patients, suffering from a particularly malignant cervical tumour, have embarked on a new form of radiotherapy. This first clinical trial, based on boron neutron capture therapy (BNCT), is the result of 10 years of collaboration between the leading specialists in Europe. This advance in radiotherapy has been made possible thanks to the equipment and knowhow of the Joint Research Centre (JRC), Petten.


Every year, throughout the world, more than six million treatments, diagnoses and therapies are carried out in departments of nuclear medicine with the help of "European" radioisotopes. This "raw material" for nuclear medicine is produced by the High Flux Reactor (HFR) of the Institute for Advanced Materials (IAM) of the Joint Research Centre (JRC) in Petten (Netherlands). Originally intended solely for research in nuclear fusion and fission, the HFR has now discovered a second vocation.

From fusion to nuclear medicine
The HFR is a 45 MW reactor intended initially for conducting experiments on nuclear materials and fuels in the context of European civil programmes. Over the last few years, its scope has been extended to include medicine, and in particular the production of radioisotopes and boron neutron capture therapy, which is a very specialised form of radiotherapy. More than a third of its capacity is used for the production of radioisotopes employed mainly in the treatment of cancers, and it is now the principal supplier of such isotopes in Europe.

While it is true that the discovery of boron neutron capture dates back more than half a century, its application in the field of medicine is characterised by decades of trial and error. As long ago as 1936, only four years after the American biophysicist J. Chadwick discovered neutrons, G.L. Locher proposed that one of the special features of neutrons be used in the therapeutic domain. Subjecting boron atoms to low-energy neutron radiation (thermal neutrons) causes the boron nuclei to disintegrate into alpha particles and lithium isotopes with a kinetic energy of 2.5 MeV. When this disintegration occurs in the malignant cells, the energy generated is sufficient to destroy them without damaging the neighbouring cells, since the range of the particles is only 10 microns.

At the heart of the cells
"From a clinical point of view, however, BNCT only becomes an attractive proposition if a sufficient dose of thermal neutrons reaches the target cells and if the concentration of boron is high in the tumour and low in the surrounding healthy tissue," explains Raymond Moss, the scientist responsible for the BNCT programme at the HFR. These two constraints help to explain the long years of preparation and the failures associated with the initial tests of BNCT in the United States.

"Since the early 1980s, there has been a better understanding of the biology of boron neutron capture therapy, and major progress has been made in the field of boron compounds and neutron beams," adds Wolfgang Sauerwein of the University of Essen (Germany), the clinician responsible for treating patients at Petten. "Before the first irradiations carried out with the help of the HFR, numerous pharmaco-kinetic tests had been conducted over the previous 10 years - with the support of the BIOMED I programme - by the research centres associated with this experiment." These tests made it possible to select a boron-sodium compound found in the cancerous cells of cerebral tumours, but not in the cells of a healthy brain. In parallel, the HFR researchers developed a process for the production of neutron beams of sufficiently high energy to reach deep-seated cells.

This double-edged European research work has enabled us to take a step forward in our approach to cancer treatment. BNCT is currently being tested on cases of glioblastoma multiforme, a brain tumour that recurs persistently, shows little response to conventional treatments and affects 15 000 Europeans each year.

Inauguration of the radiotherapy centre at the Joint Research Centre (JRC), Petten.

First clinical trials
This European project entered phase I clinical trials in October 1997. Four groups of 10 patients from five countries (Germany, Netherlands, France, Switzerland and Austria) were selected for these trials which are being conducted under the control of the NDDO (New Drug Development Office) of the EORTC (European Organisation for Research and Treatment of Cancer) and to be funded under the Biomed II programme. Between two and six weeks after surgery in their country of origin, the patients - for whom existing known treatments offer no further hope - are transferred to the Free University of Amsterdam Hospital. For a period of four days they are taken to the HFR for daily treatment lasting 20 minutes and carried out by specialists from the University of Essen. They then return to their own country for intensive monitoring.

"The aim of the present study is to assess the toxicity of the treatment and to establish the tolerance of the healthy tissue," explains Wolfgang Sauerwein. "If we were to find evidence of a therapeutic effect, that would of course be marvellous, but concentration on anti-cancerous activity proper is not due to commence until the next stage, i.e. the phase II tests."

JRC Research : Institute for Advanced Materials
Biomed II