The ANDANTE project: a multidisciplinary approach to neutron RBE

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1 The ANDANTE project: a multidisciplinary approach to neutron RBE Andrea Ottolenghi, Klaus Trott, Giorgio Baiocco, Vere Smyth Università degli Studi di Pavia, Italy On behalf of the ANDANTE project MELODI 2013, 10 October, Brussels

2 ANDANTE (" Multidisciplinary evaluation of the cancer risk from neutrons relative to photons using stem cells and the induction of second malignant neoplasms following paediatric radiation therapy ) Funded by Euratom FP7 Began January 2012, runs for 4 years MELODI 2013, 10 October, Brussels

3 WP1 Management and administration MCG WP6 Scientific coordination SAC WP5 Training and dissemination All WPs Project Board WP2 T2.1 Experimental beam characterisation Measurements Simulations T2.2 Neutron field characterisation in proton therapy beams WP3 T3.1 Salivary/thyroid stem cells T3.2 Breast stem cells T4.1 Clinical neutron field reconstruction WP4 T4.2 Risk model development T4.3 Proof of principle study Loma Linda data T2.3 Track structure modelling T3.3 Model validation and fitting T4.4 Prospective study design

4 Workpackage 2: Physical measurement and modelling of neutron fields The purpose of this WP is Characterisation of the experimental radiation beams and determination of full radiation field at the point of interest; Measurement and modelling of neutron fluence and energy spectra out of the treatment field in proton therapy beams; Development of a track structure model of the interactions of charged particles in the experimental beams with the macromolecules within cells. MELODI 2013, 10 October, Brussels

5 UNIPV-DFNT neutrons ICRP 103 M m.f.p. few cm Initial energy distributions, N p ( ) for six ions produced by the interactions of 1-MeV neutrons with tissue (Caswell and Coyne, 1972) (+ other particles including photons!) Mean free path for energy transfer reactions of neutrons and photons in dry air and water We need to (from the HLEG): carry out mechanistic studies on early and late responses to different radiation types and dose rates starting from physical interactions Ottolenghi et al, ANDANTE kick-off meeting, Pavia, January 2012

6 Among the important aspects of secondary charged particles generated by nuclear interactions, there are the ranges and their generation within the biological targets 65 kev proton tracks (range ~1 μm) randomly generated in a cell nucleus - total dose of 1 Gy -

7 65 kev proton tracks (range ~1 μm) randomly generated in a cell nucleus - total dose of 1 Gy -

8 Neutron exposures at PTB, Braunschweig, Germany 1. pilot experiments with broad spectrum n beam already performed in July 2013 Performed irradiations: HighDoseRate Gy / min (2 dose points): * 1 Gy (10 minutes) * 0.5 Gy (5 minutes) LowDoseRate Gy/min (1 dose point): * 1 Gy (333 min) * check stem cell response to various doses of neutrons * test the dose-rate effect * salivary gland cells, mammary cells were used 2. future irradiations with quasi-monoenergetic neutron beams foreseen next year! MELODI 2013, 10 October, Brussels 8

9 1. Pilot - broad beam - set-up and simulations (PHITS) - source: (d,n) reaction on a thick Be target, Eprimary(d) = 13.5 MeV - <En>~ 5-6 MeV, En mainly contributing to the absorbed dose < 10 MeV - broad spectrum: reduced influence of sharp resonances in the n cross section! H.J.Brede et al., NIM A274 (1989), 332. Be converter collimator setup - G.Dietze et al., IAEA 371/14 (1984), 203. rotating holder for 7 PMMA cell containers MELODI 2013, 10 October, Brussels 9

10 1. Pilot - broad beam - set-up and simulations (PHITS) - source: (d,n) reaction on a thick Be target, Eprimary(d) = 13.5 MeV - <En>~ 5-6 MeV, En mainly contributing to the absorbed dose < 10 MeV - broad spectrum: reduced influence of sharp resonances in the n cross section! H.J.Brede et al., NIM A274 (1989), 332. Be converter collimator setup - G.Dietze et al., IAEA 371/14 (1984), 203. rotating holder for 7 PMMA cell containers MELODI 2013, 10 October, Brussels 10

11 1. Pilot - broad beam - set-up and simulations (PHITS) neutron flux n energy distr. at source - (10 x 10) cm 2 n field at reference 80 cm distance - dose rate controlled adjusting primary beam current - dose homogeneity checked through PHITS simulations, and also direct measurement! - spectral fluence of secondary charged particles delivering dose to cells (ICRU 44 soft tissue) simulated needed input for track structure model and initial damage calculations! MELODI 2013, 10 October, Brussels 11

12 2. Future irradiation - monoe beams - n spectral fluence - AIR - Hum. blood - Kerma in blood ongoing PHITS simulations! 0.4 MeV 1.2 MeV ICRP MeV 14.8 MeV MELODI 2013, 10 October, Brussels 12

13 Workpackage 3: Relative carcinogenesis of neutrons on stem cells The objective of WP3 is to get insights into how low and moderate doses of neutrons can influence the proliferation, differentiation and genome instability of stem cells and are therewith involved in radiation-induced carcinogenesis. After irradiation with either neutrons or with photons, doseresponse relationships of different stem cell populations will be investigated in vitro and in vivo: Determination of radiation effects on salivary and thyroid gland stem cells (task 3.1) Determination of radiation effects on breast tissue stem cells (task 3.2) Validation of track structure model (task 3.3) MELODI 2013, 10 October, Brussels

14 Universitaet Rostock (UROS), Germany Department of Radiotherapy and Radiation Oncology From isolation to assessment of dose response Isolation of glandular cells from reduction mammoplasty 3. Separation of desired cells using MACS (Magnetic activated cell sorting) 4. Irradiation of stem cells with X-rays or neutrons 2. Selection of stem cells through culture conditions Brussels, 28. January 2013 in vitro in vivo

15 Experimental set-up X-ray irradiation (UMCG) Neutron irradiation (Braunschweig) Isolation stem cells Transplantation mice Transplantation mice Establishment of model 1. Isolation of salivary gland stem/progenitor cells 2. Development of thyroid stem cell assay 3. Irradiation of stem/progenitor cells Photons Neutrons 4. Assessment of transformation

16 Workpackage 4: Relative carcinogenesis of neutrons on humans using paediatric data The aim of WP4 is to: Develop a methodology for reconstruction of neutron dose and energy outside the treatment volume in proton therapy patients; Develop a predictive neutron dose-risk model in order to validate neutron RBE values using proton therapy data; Proof of principle study for validation of neutron dose-risk model using paediatric radiotherapy data; Design and if possible initiate a prospective multi-centre epidemiological study to validate neutron RBE models and investigate more general tumorigenesis risks from neutrons. MELODI 2013, 10 October, Brussels

17 Review of epidemiological studies on second malignant neoplasms (SMN) after radiotherapy in childhood Purpose: To our knowledge, first systematic review on SMN risks after radiotherapy in children only Assessment of the validity of clinical data and the predicitve cancer risk model developed in Task 4.2 Use of these results to design and if possible initiate a prospective epidemiological study using paediatric proton therapy data Material and medthods: 45 studies included from 2001 until present Estimation of the magnitude of the effect of high-dose exposure by comparing collected estimates with the estimates from the Life Span Study (LSS) of the Japanese atomic bomb survivors Development of a set of criteria to estimate SMN location (in-field, out-field, border) and stratification of studies MELODI 2013, 10 October, Brussels

18 Task 4.4: Prospective epidemiological study Design/Initiation of a prospective epidemiological study using paediatric proton therapy data collected from multiple proton centres world-wide Statistical analysis for estimation of key parameters such as required cohort size, follow-up time, and assessing critical areas of uncertainty, etc. Collaboration with the National Cancer Institute, USA (coordination of the treatment and follow-up data): contact had been made with the NCI about future work with them and Reinhard plans to put in a grant for a funded dosimetry study next year. Exploration of the possibility of deriving cancer risks related to neutrons independently of the RBE formalism Investigation of problems associated with patient confidentiality, followup (more than 10 years), patient geometry, SMN location, potential confounders etc. MELODI 2013, 10 October, Brussels

19 When effective dose is not effective How should we express the physical quantity of neutron dose (grays) when it is modified by relative biological effectiveness (RBE)? The special name and symbol sievert (Sv) instead of gray (Gy) has been introduced for use with the regulatory quantity effective dose. But to avoid confusion Sv should not be used with absorbed doses multiplied by other weighting factors, such as a neutron RBE assumed for a particular circumstance. In ANDANTE the neutron risk is not being evaluated using the standard effective dose formalism. MELODI 2013, 10 October, Brussels

20 Conclusions We are almost half way through the project Secondary charged particles from neutrons are being simulated in the experimental conditions The track structure code is being developed to include very low energy ions (secondaries from neutrons) First irradiation of stem cells with neutrons have been performed at PTB A review of epidemiological studies on second malignant neoplasms after radiotherapy in childhood was performed Measurements at Loma linda and PSI proton facilities are being performed MELODI 2013, 10 October, Brussels

Figure 1.1 PHITS geometry for PTB irradiations with: broad beam, upper panel; mono energetic beams, lower panel. Pictures of the setups and of the

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