Neutrons for medicine

There are a lot of definitions of cancer: in a few words one could say that it represents a group of diseases characterized by the growth and uncontrolled diffusion of abnormal cells. Considering the number of deaths at the world level in 2005 (50 millions), cancer is responsible of 7.6 millions (that is 13%) with an expected increase to 11.4 millions in 2030. The innovations in the field of radiotherapy, chemotherapy, surgery and their combined applications have allowed to maintain these numbers under control. Radiation therapy has been used for the treatment of cancer and other diseases for approximately 100 years. As early as 1897, two years after the discovery by Wilhelm Conrad Rontgen, it was concluded that X-rays could be used for therapeutic as well as diagnostic purposes. But nearly 30 years were necessary to make radiotherapy world wide diffused: in fact, X-rays moved into clinical therapeutic routine only in the early 1920s. Since the first uses of radiation to treat cancer, important changes have been made in this field and several developments have been accomplished, both from the instrumental (new types of linear accelerators to generate higher energy radiation beams) and medical (different types of ionizing radiation and progress in treatment planning) points of view. On the other hand there is a series of tumours whose survival curve has not varied in time both in absolute and incremental terms: extended tumours (such as the ones of stomach, liver and lung), tumours localized near or in vital organs (such as the glioblastoma multiforme (GBM) in the brain), radioresistant tumours (such as melanoma). The research for new ways of treatment, together with the discovery of neutrons in 1932 and the studies concerning their properties, inspired in the American biophysicist G. L. Locher in 1936 the attempt to use neutron beams in radiotherapy in the so-called NCT (Neutron Capture Therapy) first and BNCT (Boron Neutron Capture Therapy) then. BNCT could (and the conditional is a must) represent a hope for all the cases still lacking a survival improvement. BNCT is a technique that in principle joins the localization capability of radiotherapy and the specificity of chemotherapy, allowing a selective release of the dose only to cancer cells, without damaging the surrounding healthy tissues. This technique is based on the irradiation with thermal and epithermal neutrons of a boronated compound (the so called carrier) selectively concentrated in tumor cells. Following the capture of a neutron, the 10B isotope emits high LET particles (an and a 7Li ion) that release their whole energy in the cell where the boron atom was present at the moment of the irradiation. The first BNCT experimental treatments were performed during the '50s. Since then, BNCT has met ups and downs in its history because of a physical and a biological reason: from the physical point of view, the features of the neutron beam (a flux >5 X 108 n cm-2 s-1 with an energy <10 keV) identify nuclear reactors as the only adequate sources; from the biological point of view, the carriers that bring the 10B inside the cell are not selective but exploit the greater metabolism of the cancer cells with respect to the healthy ones. BNCT has been performed in nuclear reactors in the United States (MIT, WSU), in Japan (KURRI, JRR-4), in Argentina (RA-6), in Europe (JRC - the Netherlands, Medical AB - Sweden, FiR1 - Finland) for activities of Phase I (toxicity) and of Phase II (ef_cacy); no center has started a Phase III protocol (BNCT tests randomized with respect to the standard techniques). Possible patients for BNCT treatments have to submit the request for the therapy to the International Ethic Committee who analyzes all the other possibilities before agreeing to a non standard treatment, a fact which limits the number of patients and thus the available statistics. To understand completely the impact and the advantages of BNCT with respect to other techniques, it is necessary to study the boron concentration, its sub-cellular distribution, its fixation molecular sites, its transport and its exchange dynamics in several biological samples, possibly in a user friendly environment, easily accessible and with a low photon or particle background. In other words, one of the main tasks for the BNCT development in terms of clinical treatments is the study of the pharmacokinetics of the carrier. This requires the development of reliable methods for monitoring the boron concentration in healthy and tumour cells. This study has to proceed in parallel with the design of in-hospital radiation sources. The project of a treatment plan involves the work of medical doctors, oncologists, biology and chemistry experts, physicists; the work of such a pool of people is not easy to organize outside the hospital in a complicated environment such as the one of a nuclear reactor. Moreover, also the test of new carriers or the trials on new organs have to be inserted in the schedule of a reactor increasing times and costs. This thesis locates itself in the field of BNCT facing both the problems that still limit its becoming a standard therapy. The work has been performed both at a nuclear reactor and in a hospital environment collaborating with some of the most important groups in Italy involved with BNCT. The first chapter focuses on what cancer is, how it develops and how it can be cured summarizing the three main treatment modalities (surgery, chemotherapy and radiotherapy) and analyzing the brain cancer as an example of an illness still without hope. The last part of the chapter concerns the rationale of BNCT, whose ingredients are described in detail in chapter 2, which focuses both on the boron carrier and the neutron beam. Chapter 3 summarizes the features of a nuclear reactor neutron beam for BNCT, describing the instruments and the procedure to characterize such a beam. In particular, the chapter focuses on the measurements performed on the epithermal column of the TAPIRO reactor (ENEA, Casaccia, Italy) with thermoluminescent detectors. The data taking and analysis procedure are described in detail in order to give an idea of the pros and cons of such non real time detectors. Chapter 4 moves in the opposite direction, considering the development of a hospital based BNCT beam both from the industrial point of view (presenting as an example the proton + Li target accelerator proposed by IBA) and the completely different approach of the PhoNeS (ProtoNeutron Source) project, which exploits a standard radiotherapy linac producing neutrons via the Giant Dipole Resonance. The chapter describes in detail the PhoNeS prototype and the measurements to characterize the beam, presenting real time and innovative systems that can be used thanks to the pulsed nature of the linac beam which allows to work in a background free environment. The last part of the chapter is dedicated to the application of this beam to the study of the boron concentration in biological samples (urine and blood) to obtain the kinetic curves (that is the boron concentration as a function of the time from the administration) for patients undergoing BNCT treatments. This same .imaging system. has been applied to the study of another possible organ that could bene_t of BNCT, that is the lung.