A Compact Neutron Generator for the Niort® Treatment of Severe Solid Cancers

Main Article Content

Maurizio Martellini Massimo Sarotto Ka-Ngo Leung Giuseppe Gherardi

Abstract

In the last four years, TheranostiCentre S.r.l., Berkion Technology LLC and ENEA have patented and fabricated a first prototype of a Compact Neutron Generator (CNG) currently under testing in the ENEA laboratories. Besides the usual applications in the field of materials irradiation, this CNG - producing neutrons of 2.45 MeV energy through the deuterium-deuterium (DD) fusion reaction - was conceived for the neutron irradiation of the solid cancer’s tumour bed by means of the Intra-Operative Radiotherapy (IORT) technique, the so-called neutron-IORT (nIORT®). The DD-CNG is self-shielded and light-weight (~120 kg) making possible its remote handling by a robotic arm. Accurate Monte Carlo simulations, modelling the CNG and the “open wound” biological tissues near its irradiation window, demonstrated that the apparatus operated at 100 kV-10 mA supplies a neutron flux ~108 cm-2 s-1 and can deliver equivalent dose rates ~2 Gy (RBE)/min. Hence, it can administer very high dose levels in limited treatment times.


This article briefly summarizes the main findings of this collaborative research study, the clinical rationales underpinning the nIORT® idea and the potential performances of the DD-CNG for the treatment of solid cancer pathologies. Indeed, the CNG can be installed in an operating room dedicated to nIORT® treatments, without posing any environmental and safety issues. Monte Carlo simulations have been carried out by envisioning the CNG equipped with an IORT applicator, that is an applicator pipe with a tuneable diameter to be inserted in the surgical cavity. By foreseeing the clinical endpoints of the standard IORT protocols, the irradiation performances for potential nIORT® treatments - obtained with an applicator pipe of 6 cm diameter - are here reported for different regimes: from 10 up to 75 Gy (RBE), that can be administered in a single session of about 4 to 30 minutes. Besides the dose peak in the centre of the tumour bed, the almost isotropic neutrons emission allows to irradiate its surroundings side-walls – usually filled by potential quiescent cancer cells – and therefore reducing the chances of local recurrences by improving the local control of the tumour. The rapid decrease in tissues depth of the dose profile (in few centimetres) will spare the neighbouring organs at risk from harmful radiations. Thus, the DD-CNG apparatus developed for nIORT® applications can potentially improve the resectability rate of a given neoadjuvant cancer treatment and, generally, could satisfy all five R’s criteria of radiotherapy. Furthermore, in comparing with the current IORT techniques with electrons or low-keV Xrays, the nIORT® exploiting a high-flux neutrons beam of 2.45 MeV energy could lead to some significant clinical advantages due to its high linear energy transfer (~ 40 keV/mm as average) and significantly higher relative biological effectiveness (@16) than all other forms of ionizing radiation.

Article Details

How to Cite
MARTELLINI, Maurizio et al. A Compact Neutron Generator for the Niort® Treatment of Severe Solid Cancers. Medical Research Archives, [S.l.], v. 11, n. 3, mar. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/3799>. Date accessed: 02 may 2024. doi: https://doi.org/10.18103/mra.v11i3.3799.
Section
Research Articles

References

1. Sethi A, Emami B, Small W J, Thomas T O. In-traoperative Radiotherapy With INTRABEAM: Technical and Dosimetric Considerations. Frontiers in Oncology. 2018;8. doi:10.3389/fonc.2018.00074
2. Severgnini M, De Denaro M, Bortul M, Vidali C, Beorchia A. In vivo dosimetry and shielding disk alignment verification by EBT3 GAFCHROMIC film in breast IOERT treatment. J. Appl. Clin. Med. Phys. 2014;16(1):5065. doi:10.1120/jacmp.v16i1.5065
3. Philippson C, Larsen S, Simon S, Vandekerkhove C, De Caluwe A, Van Gestel D, Chintinne M, Veys I, De Neubourg F, Noterman D, Roman M, Nogaret JM, Desmet A. Intraoperative electron radiothera-py in early invasive ductal breast cancer: 6-year median follow-up results of a prospective mo-nocentric registry. Breast cancer RES. 2022;24, 83. doi:10.1186/s13058-022-01582-4
4. Martellini M, Gherardi G. Apparatus for the intraoperative radiotherapy. 2019; European Pa-tent EP 3 522 177 B1.
5. Seneviratne D, Advani P, Trifiletti D M, Chumsri S, Beltran C J, Bush A F, Vallow L A. Exploring the Biological and Physical Basis of Boron Neutron Capture Therapy (BNCT) as a Promising Treatment Frontier in Breast Cancer. Cancers. 2022;4(12),3009. doi:10.3390/cancers14123009
6. Hervé M, Sauzet N, Santos D. On the eptiher-mal neutron energy limit for Accelerator-Based Boron Neutron Capture Therapy (AB-BNCT): Study and impact of new energy limits. European Journal of Medical Physics; 2021;88:148-157. doi:10.1016/j.ejmp.2021.06.016
7. Nishitani T, Yoshihashi S, Tanagami Y, Tsuchida K, Honda S, Yamazaki A, Watanabe K, Kiyanagi Y, Uritani A. Neutronics Analyses of the Radiation Field at the Accelerator-Based Neutron Source of Nagoya University for the BNCT Study. J. Nucl. Eng. 2022;3(3):222-232; doi:10.3390/jne3030012
8. Tillery H, Moore M, Gallagher K J, Taddei P G, Leuro E, Argento D, Moffitt G, Kranz M, Carey M, Heymsfield S B. Personalized 3D-printed anthro-pomorphic whole-body phantom irradiated by protons, photons, and neutrons. Biomed. Phys. Eng. Express. 2022;8(2),027004. doi:10.1088/2057-1976/ac4d04
9. Annals of the International Commission on Radi-ological Protection. 2007; ICRP 103(37); ISSN 0146-6453, ISBN 978-0-7020-3048-2
10. Vignard J, Mirey G, Salles B. Ionizing-radiation induced DNA double-strand breaks: a direct and indirect lighting up. Radiother. Oncol. 2013;108(3):362-9. doi:10.1016/j.radonc.2013.06.013
11. Jones B. Fast neutron energy based modelling of biological effectiveness with implications for proton and ion beams. Phys. Med. Biol. 2021;66, 045028. doi:10.1088/1361-6560/abddd0
12. Van de Kamp G, Heemskerk T, Kanaar R, Es-sers J. DND Double Strand Break Repair Pathways in response to different types of ionizing radiation. Frontiers in Genetics, Sec. Human and Medical Genomics. 2021;12:738230. doi:10.3389/fgene.2021.738230
13. Shibata A, Conrad S, Birraux J, Geuting V, Barton O, Ismail A, Kakarougkas A, Meek K, Taucher-Scholz G, Lobrich M, Jegg P A. Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO Journal (Eu-ropean Molecular Biology Organization). 2011;30:1079-1092.
14. Rini F, Hall E J, Marino S. A. The Oxygen En-hancement Ratio as a Function of Neutron Energy with Mammalian Cells in Culture, Radiation Re-search. 1979;78(1):25-37. doi: 10.2307/3575004
15. Antonovic L, Lindblom E, Dasu A, Bassler N, Furusawa Y, Toma-Dasu I, Clinical oxygen en-hancement ratio of tumors in carbon ion radiother-apy: the influence of local oxygenation changes. Journal of Radiation Research. 2014;55(5):902-911. doi:10.1093/jrr/rru020
16. Dousset M H, Hamard J, Ricourt A. Distribution of the dose from neutrons in a thin sample of wet tissue as a function of linear energy transfer (LET). Phys. Med. Biol. 1971;16(3):467-478. doi:10.1088/0031-9155/16/3/008
17. Bleddyn J. Clinical Radiobiology of Fast Neu-tron Therapy: What Was Learnt? J. Front. Oncol. Sec. Radiation Oncology. 2020;10. doi:10.3389/fonc.2020.01537
18. Jones B. Clinical Radiobiology of Fast Neutron Therapy: What Was Learnt? Frontiers in Oncolo-gy. 2020;10. doi:10.3389/fonc.2020.01537
19. Gamy S, Ruhm W, Zankl M, Wagner F M, Pa-retzke H G. First steps toward a fast-neutron ther-apy planning program. Radiation Oncology. 2011;6:163. doi:10.1186/1748-717X-6-163
20. Fernandez-Palomo C, Chang S, Prezado Y. Should Peak Dose Be Used to Prescribe Spatially Fractionated Radiation Therapy? A Review of Pre-clinical Studies. Cancers; 2022;14,3625. doi:10.3390/cancers14153625
21. Wilson J, Hammond E M, Higgins G S, Peters-son K, Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold? Frontiers in Oncology. 2020;9. doi:10.3389/fonc.2019.01563
22. Herskind C, Ma L, Liu Q, Zhang B, Schneider F, Veldwijk M R, Wenz F. Biology of high single dos-es of IORT: RBE, 5 R’s, and other biological as-pects. Radiation Oncology. 2017:12:24. doi:10.1186/s13014-016-0750-3
23. Martellini M, Gherardi G, Leung K, Leug J K, Sarotto M, Rizzo A. Multi Purpose Compact Appa-ratus for the Generation of a high-flux of neutrons, particularly for Intraoperative Radiotherapy. 2021; Int. Patent PCT/IT2021/000032. WIPO (World Intellectual Property Organisation) 2023;WO 2023/281539 A1
24. LINCER project. Laboratorio per la caratterizzazione di Irradiatori Neutronici Compatti in Emilia Romagna. Funded by Emilia Romagna with “Legge Regionale 27/12/2018 N.25, DGR N. 545/2019 – CUP I74I19000360003”. 2020-2022
25. Leung K G. New compact neutron generator system for multiple applications. Nuclear Technol-ogy. 2020;206(10):1607-14. doi:10.1080/00295450.2020.1719800
26. Pelowitz B. MCNP6 user’s manual. 2013; Tech. Rep. Los Alamos National Lab LA-CP-13-00634 Rev. 0
27. Obložinský P. Special Issue on Nuclear Data. J. Nuclear Data Sheets. 2018;148:1-420; ISSN: 0090-3752
28. Sarotto M. Parametric MCNP analyses to ad-dress the design of a neutron collimator for high-flux compact DD sources to be used in cancer ra-diotherapy. 2021; Tech. Rep. ENEA SICNUC-P000-044
29. Kramer R, Zankl M, Williams G, Drexler G. The calculation of dose from external photon exposures using reference human phantoms and Monte-Carlo: part I. The male (Adam) and female (Eva) adult mathematical phantom. 1982; Tech. Report GSF- S-885 (Germany)
30. Baiocco G, Barbieri S, Babini G, Morini J, Al-loni D, Friedland W, Kundrát P, Schmitt E, Puchalska M, Sihver L, Ottolenghi A. The origin of neutron biological effectiveness as a function of energy. Scientific Reports. 2016;6:34033. doi:10.1038/srep34033
31. Liu Q, Schneider F, Ma L, Wenz F, Herskind C. Relative Biologic Effectiveness (RBE) of 50 kV X-rays measured in a phantom for intraoperative tumor-bed irradiation. Int. J. Radiat. Oncol. Biol. Phys. 2013;85(4):1127-33. doi:10.1016/j.ijrobp.2012.08.005
32. Sarotto M, Martellini M. MCNP analyses of the 100 kV D-ion-based compact neutron source: irra-diation performances for nIORT® treatments with different irradiation window diameters. 2022; Tech. Rep. ENEA SICNUC-P000-045
33. Pilar A, Gupta M, Laskar S G, Laskar S, In-traoperative radiotherapy: review of techniques and results. ecancer medical science. 2017;11(750). doi:10.3332/ecancer.2017.750
34. Hashemi S. Comparison of IORT (Radical and Boost Dose) and EBRT in Terms of Disease-Free Survival and Overall Survival according to Demo-graphic, Pathologic, and Biological Factors in Pa-tients with Breast Cancer. J. of Surgical Oncology. 2021;2476527. doi:10.1155/2021/2476527
35. International Atomic Energy Agency. Current status of neutron capture therapy. 2001; IAEA TECDOC-1223
36. Mladenova V, Mladenov E, Chaudhary S, Stuschke M, Iliakis G. The high toxicity of DSB-clusters modelling high-LET-DNA damage derives from inhibition of c-NHEJ and promotion of alt-EJ and SSA despite increases in HR. J. Frontiers in Cell and Developmental Biology. 2022;10:1016951. doi:10.3389/fcell.2022.1016951
37. Mahaney B L, Meek K, Lees-Miller S P. Repair of Ionizing radiation-induced DNA double strand breaks by non-homologous end-joining. Biochemi-cal J. 2009;417(3):639-50. doi:10.1042/BJ20080413
38. Niemantsverdriet, Van Goethem M J, Bron R, Hogewerf W, Brandenburg S, Langendijk J A, Van Luijk P, Coppes R P. High and Low LET Radiation Differentially Induce Normal Tissue Damage Sig-nals. Int. J. Radiation Oncol. Biol. Phys. 2012;83(4):1291-7. doi:10.1016/j.ijrobp.2011.09.057
39. Busato F, El Khouzai B, Mognato M. Biological Mechanisms to Reduce Radioresistance and In-crease the Efficacy of Radiotherapy: State of the Art. Int. J. of Molecular Science. 2022;23(18),10211. doi:10.3390/ijms231810211
40. Baskar R, Dai J, Wenlong N, Yeo R, Yeoh K W. Biological response of cancer cells to radiation treatment. Frontiers in Molecular Biosciences; 2014;1. doi:10.3389/fmolb.2014.00024
41. Wang C, Smith R W, Duhig J, Prestwich W V, Byun S H, McNeill F E, Seymour C B, Mothersill C E. Neutrons do not produce a bystander effect in zebrafish irradiated in vivo. Int. J. Radiat. Bi-ol. 2011;87(9):964-73, doi:10.3109/09553002.2011.584939
42. Trivillin V A, Pozzi E C, Colombo L L, Thorp S I, Garabalino M A, Hughes A M, González S J, Fa-rías R O, Curotto P, Santa Cruz G A, Carando D G, Schwint A E. Abscopal effect of boron neutron capture therapy (BNCT): proof of principle in an experimental model of colon cancer. Radiat. Environ. Biophys. 2017;56:365-375; doi:10.1007/s00411-017-0704-7
43. Lee Y S, Kim H S, Cho Y, Lee I J, Kim H J, Lee D E, Kang H W, Park J S. Intraoperative radiation therapy induces immune response activity after pancreatic surgery. BMC Cancer. 2021;21(1):1097. doi:10.1186/s12885-021-08807-3
44. Gaponova A V, Rodin S, Mazina A A, Vol-chkov P V. Epithelial–Mesenchymal Transition: Role in Cancer Progression and the Perspectives of Anti-tumor Treatment. Acta Naturae. 2011;12(3):4-23. doi:10.1093/jrr/rru020
45. Roche J. The Epithelial-to-Mesenchymal Transi-tion in Cancer. Cancers. 2018;10,52. doi:10.3390/cancers10020052
46. Gapanova A V, Rodin S, Mazina A A, Vol-chkov V. Epithelial–Mesenchymal Transition: Role in Cancer Progression and the Perspectives of Anti-tumor Treatment. Acta Naturae. 2020;12(46).
47. Tian H, Lyu Y, Yang Y G, Hu Z. Humanized rodent models for cancer research. Frontiers in Oncology. 2020;10. doi:10.3389/fonc.2020.01696
48. Cromheecke M, Grond A J K, Szabo B G, Hoekstra H J. Short- and long-term histopathologi-cal changes in the canine liver following single high-dose intraoperative radiation therapy (IORT). International Journal of Radiation Biology. 1999;75(11). doi:10.1080/095530099139304
49. Bradley W.M., Schlipp D., Khatibzadeh S.M., Electronic brachytherapy used for the successful treatment of three different types of equine tumours. Equine Veterinary Education, 06 August 2015,
doi:org/10.1111/eve.12420
50. Suemeyra Can, Oezge Atilla and Didem Karacetin, Calculated and measured radiation dose for the low energy soft accent eBT X-ray source, BMC Research Notes 2023, 16 (25),
doi:org/10.1186/s13104-023-06287-1

Most read articles by the same author(s)