The ANDANTE project: progress towards a re-evaluation of the risk from scattered neutrons during proton therapy

It is well known that proton therapy generates a small but significant exposure to scattered neutrons. The success of proton treatment, particularly paediatric treatments, leads to the concern about second cancers arising in later life from the neutron exposure. However there are many difficulties involved with estimating the risk of cancer induction from exposure to neutrons. The usual approach to risk assessment is through the concept of relative biological effectiveness (RBE) of neutrons compared to photons, since the risk from photon exposure is much better known. RBE has been evaluated using cellular and animal models. But this causes difficulties in applying the concept to humans. The ANDANTE project is evaluating RBE taking a new approach using three different disciplines in parallel: Physics: a track structure model is used to contrast the patterns of damage to cellular macro-molecules from neutrons compared to photons. The simulations reproduce the same energy spectra as are used in the other two approaches. Stem cell radiobiology: stem cells from thyroid, salivary gland, and breast tissue are given well characterised exposures to neutrons and photons. A number of endpoints are used to estimate the relative risk of damage from neutrons compared to photons. As well, irradiated cells will be transplanted into mice to investigate the progression of the initial radiation effects in stem cells into tumours in a physiological environment. Epidemiology: the relative incidence rates of second cancers of the thyroid, salivary gland, and breast following paediatric radiotherapy (conventional radiotherapy for photons and proton therapy for neutrons) are investigated in a pilot single-institution study, exploring the possible design of a multi-institution prospective study comparing the long-term out-of field and in-field effects of scanned and scattered protons. The results will be used to validate an RBE-based risk model developed by the project, and validate the corresponding RBE values. The ANDANTE project has been underway since January 2012, and has now passed the halfway point. Preliminary results can now be reported in each of the approaches. The experimental beams to be used for exposure of stem cells have been characterised and modelled using the Monte Carlo Code PHITS. The results have been used to design an exposure container for stem cells with satisfactory dose uniformity. The secondary charged particle fluences and spectra have been modelled for input into the track structure model. An analytical method is being developed that will allow the dose from scattered neutrons received by a proton therapy patient at any part of the body at risk of second cancer induction. Work to date has involved measurements on anthropomorphic phantoms and Monte Carlo modelling to provide base data for development of the analytical method. Stem cells from thyroid, salivary gland, and breast tissue have all been successfully isolated and propagated. A first set of exposures to broad spectrum neutrons and to 200kV x-rays has been completed in order to assess the incidence of damage at different doses and dose-rates. Part of the cell population has been transplanted into mice and it is planned to excise these nodules at pre-determined times up to one year after transplantation and perform detailed histopathological and molecular investigations of the long-term progeny of irradiated stem cells, specifically looking for pre-malignant lesions and signs of malignancy. Initial results are currently being analysed. A predictive neutron dose-risk model is being developed, based on the known risk of second cancers following radiotherapy with photons modified by an RBE derived from the project results. In order to gain the base photon risk data a new review of epidemiological studies on second malignant neoplasms (SMN) after radiotherapy in childhood has been performed which included 45 publications from 2001 until present. The methodology needed for an epidemiological validation of the risk model is being trialled on the database at the Loma Linda Proton Treatment Center.