Original paper| Volume 67, P9-19, November 2019

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The essential role of radiobiological figures of merit for the assessment and comparison of beam performances in boron neutron capture therapy

Published:October 11, 2019DOI:


      • Formal definition of the therapeutic potential and versatility of a BNCT beam.
      • Derivation of a head and neck cancer TCP model for non-uniform doses.
      • Introduction of a novel model of uncomplicated tumor control probability in BNCT.
      • Demonstration of the usefulness of the models to assess the performance of a beam.
      • Introduction of a practical and essential aid to guide treatment decisions.



      Boron Neutron Capture Therapy (BNCT) is a treatment modality that uses an external neutron beam to selectively inactive boron10-loaded tumor cells. This work presents the development and innovative use of radiobiological probability models to adequately evaluate and compare the therapeutic potential and versatility of beams presenting different neutron energy spectra.


      Aforementioned characteristics, collectively refer to as the performance of a beam, were defined on the basis of radiobiological probability models for the first time in BNCT. A model of uncomplicated tumor control probability (UTCP) for HN cancer was introduced. This model considers a NTCP able to predict severe mucositis and a TCP for non-uniform doses derived herein. A systematic study comprising a simplified HN cancer model is presented as a practical application of the introduced radiobiological figures of merit (FOM) for assessing and comparing the performance of different clinical beams. Applications involving treated HN cancer patients were also analyzed.


      The maximum UTCP proved suitable and sensitive to assess the performance of a beam, revealing particularities of the studied sources that the physical FOMs do not highlight. The radiobiological FOMs evaluated in patients showed to be useful tools both for retrospective analysis of the BNCT treatments, and for prospective studies of beam optimization and feasibility.


      The presented developments and applications demonstrated that it is possible to assess and compare performances of completely different beams fairly and adequately by assessing the radiobiological FOM UTCP. Thus, this figure would be a practical and essential aid to guide treatment decisions.

      Graphical abstract


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        • Locher G.
        Biological effects and therapeutical possibilities of neutrons.
        Am J Roent Radium Ther. 1936; 36: 1-13
        • TECDOC Series 1223
        Current status of neutron capture therapy.
        International Atomic Energy Agency (IAEA), 2001
        • Wheeler F.J.
        • Nigg D.W.
        • Capala J.
        • Watkins P.R.D.
        • Vroegindeweij C.
        • Auterinen I.
        • et al.
        Boron neutron capture therapy (BNCT): implications of neutron beam and boron compound characteristics.
        Med Phys. 1999; 26: 1237-1244
        • González S.J.
        • Cruz G.A.S.
        The photon-isoeffective dose in boron neutron capture therapy.
        Radiat Res. 2012; 178: 609-621
        • González S.J.
        • Pozzi E.C.C.
        • Hughes A.M.
        • Provenzano L.
        • Koivunoro H.
        • Carando D.G.
        • et al.
        Photon iso-effective dose for cancer treatment with mixed field radiation based on dose–response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.
        Phys Med Biol. 2017; 62: 7938-7958
        • Esposito J.
        • Colautti P.
        • Fabritsiev S.
        • Gervash A.
        • Giniyatulin R.
        • Lomasov V.N.
        • et al.
        Be target development for the accelerator-based SPES-BNCT facility at INFN Legnaro.
        Appl Radiat Isot. 2009; 67: S270-S273
        • Blaumann H.R.
        • González S.J.
        • Longhino J.
        • Cruz G.A.S.
        • Larrieu O.A.C.
        • Bonomi M.R.
        • et al.
        Boron neutron capture therapy of skin melanomas at the RA-6 reactor: a procedural approach to beam set up and performance evaluation for upcoming clinical trials.
        Med Phys. 2004; 31: 70-80
        • Kankaanranta L.
        • Seppälä T.
        • Koivunoro H.
        • Saarilahti K.
        • Atula T.
        • Collan J.
        • et al.
        Boron neutron capture therapy in the treatment of locally recurred head-and-neck cancer: final analysis of a phase I/II trial.
        Int J Radiat Oncol Biol Phys. 2012; 82: e67-e75
        • Coderre J.A.
        • Morris G.M.
        The radiation biology of boron neutron capture therapy.
        Rad Res. 1999; 151: 1-18
        • González S.J.
        • Bonomi M.R.
        • Santa Cruz G.A.
        • Blaumann H.R.
        • Larrieu O.A.C.
        • Menéndez P.
        • et al.
        First BNCT treatment of a skin melanoma in Argentina: dosimetric analysis and clinical outcome.
        Appl Radiat Isot. 2004; 61: 1101-1105
        • Menéndez P.R.
        • Roth B.M.C.
        • Pereira M.D.
        • Casal M.R.
        • González S.J.
        • Feld D.B.
        • et al.
        BNCT for skin melanoma in extremities: Updated Argentine clinical results.
        Appl Radiat Isot. 2009; 67: S50-S53
        • Sato T.
        • Masunaga S.
        • Kumada H.
        • Hamada N.
        Microdosimetric modeling of biological effectiveness for boron neutron capture therapy considering intra- and intercellular heterogeneity in 10B distribution.
        Sci Rep. 2018; 8: 988
        • Ono K.
        • Tanaka H.
        • Tamari Y.
        • Watanabe T.
        • Suzuki M.
        • Masunaga S.
        Proposal for determining absolute biological effectiveness of boron neutron capture therapy—the effect of 10B(n, α)7Li dose can be predicted from the nucleocytoplasmic ratio or the cell size.
        J Radiat Res. 2018; 60: 29-36
        • Laramore G.
        • Wheeler F.
        • Wessol D.
        • Stelzer K.
        • Griffin T.
        • Larsson B.
        • et al.
        A tumor control curve for malignant gliomas derived from fast neutron radiotherapy data: implications for treatment delivery and compound selection.
        Elsevier Science, New York1997: 580-587
        • Farías R.O.
        • Bortolussi S.
        • Menéndez P.R.
        • González S.J.
        Exploring boron neutron capture therapy for non-small cell lung cancer.
        Phys Med. 2014; 30: 888-897
        • Tommasino F.
        • Nahum A.
        • Cella L.
        Increasing the power of tumour control and normal tissue complication probability modelling in radiotherapy: recent trends and current issues.
        Transl Cancer Res. 2017; 6 (doi: 10.21037/14116): S807-S821
        • Kreimann E.L.
        • Itoiz M.E.
        • Dagrosa A.
        • Garavaglia R.
        • Farías S.
        • Batistoni D.
        • et al.
        The hamster cheek pouch as a model of oral cancer for boron neutron capture therapy studies: selective delivery of boron by boronophenylalanine.
        Cancer Res. 2001; 61: 8775-8781
        • Vairaktaris E.
        • Spyridonidou S.
        • Papakosta V.
        • Vylliotis A.
        • Lazaris A.
        • Perrea D.
        • et al.
        The hamster model of sequential oral oncogenesis.
        Oral Oncol. 2008; 44: 315-324
        • Chen Y.-K.
        • Lin L.-M.
        DMBA-induced hamster buccal pouch carcinoma and VX2-induced rabbit cancer as a model for human oral carcinogenesis.
        Expert Rev Anticancer Ther. 2010; 10: 1485-1496
        • Supsavhad W.
        • Dirksen W.P.
        • Martin C.K.
        • Rosol T.J.
        Animal models of head and neck squamous cell carcinoma.
        Vet J. 2016; 210: 7-16
        • Kato I.
        • Fujita Y.
        • Maruhashi A.
        • Kumada H.
        • Ohmae M.
        • Kirihata M.
        • et al.
        Effectiveness of boron neutron capture therapy for recurrent head and neck malignancies.
        Appl Radiat Isot. 2009; 67: S37-S42
        • Wang L.-W.
        • Chen Y.-W.
        • Ho C.-Y.
        • Hsueh Liu Y.-W.
        • Chou F.-I.
        • Liu Y.-H.
        • et al.
        Fractionated boron neutron capture therapy in locally recurrent head and neck cancer: a prospective phase I/II trial.
        Int J Radiat Oncol Biol Phys. 2016; 95: 396-403
        • González S.J.
        • Carando D.G.
        A general tumour control probability model for non-uniform dose distributions.
        Math Med Biol. 2008; 25: 171-184
        • Strigari L.
        • Pedicini P.
        • D’Andrea M.
        • Pinnarò P.
        • Marucci L.
        • Giordano C.
        • et al.
        A new model for predicting acute mucosal toxicity in head-and-neck cancer patients undergoing radiotherapy with altered schedules.
        Int J Radiat Oncol Biol Phys. 2012; 83: e697-e702
        • Stüben G.
        • van der Kogel A.J.
        • van der Schueren E.
        Biological equivalance of low dose rate to multifractionated high dose rate irradiations: investigations in mouse lip mucosa.
        Radiother Oncol. 1997; 42: 189-196
        • Provenzano L.
        • Farías R.O.
        • Longhino J.M.
        • Boggio E.F.
        • Herrera M.S.
        • Moijsecsiuck N.
        • et al.
        A prospective study to assess the performance of the improved boron neutron capture therapy facility in Argentina.
        Appl Radiat Isot. 2014; 88: 171-176
        • Auterinen I.
        • Hiismäki P.
        • Kotiluoto P.
        • Rosenberg R.J.
        • Salmenhaara S.
        • Seppälä T.
        Metamorphosis of a 35 year-old TRIGA reactor into a modern BNCT facility.
        in: Hawthorne M.F. Shelly K. Wiersema R.J. Frontiers in neutron capture therapy: Volume 1. Springer US, Boston, MA2001: 267-275
        • X-5 Monte Carlo Team
        MCNP – version 5, Vol. I: overview and theory. LA-UR-03-1987.
        Los Alamos National Laboratory, 2003
        • Koivunoro H.
        • Kankaanranta L.
        • Seppälä T.
        • Haapaniemi A.
        • Mäkitie A.
        • Joensuu H.
        Boron neutron capture therapy for locally recurrent head and neck squamous cell carcinoma: an analysis of dose response and survival.
        Radiother Oncol. 2019; 137: 153-158
        • Postuma I.
        Clinical application of accelerator-based boron neutron capture therapy: optimization of procedures, tailoring of a neutron beam and evaluation of its dosimetric performance.
        ([Ph.D. thesis]) Università degli studi di Pavia, 2016
        • Raaijmakers C.P.J.
        • Nottelman E.L.
        • Mijnheer B.J.
        • Nottelman E.L.
        Phantom materials for boron neutron capture therapy.
        Phys Med Biol. 2000; 45: 2353-2361
        • Lee J.-C.
        • Chen Y.-W.
        • Chuang K.-S.
        • Hsu F.-Y.
        • Chou F.-I.
        • Hsu S.-M.
        • et al.
        The dosimetric impact of shifts in patient positioning during boron neutron capture therapy for brain tumors.
        Biomed Res Int. 2018;
        • Farias R.
        • González S.
        MultiCell model as an optimized strategy for BNCT treatment planning.
        in: Proceedings of the 15th international congress on neutron capture therapy. 2012: 149-150 (Tsukuba, Japan)
        • White D.R.
        • Booz J.
        • Griffith R.V.
        • Spokas J.J.
        • Wilson I.J.
        Report 44.
        J ICRU. 1989;
        • Suzuki M.
        • Kato I.
        • Aihara T.
        • Hiratsuka J.
        • Yoshimura K.
        • Niimi M.
        • et al.
        Boron neutron capture therapy outcomes for advanced or recurrent head and neck cancer.
        J Radiat Res. 2014; 55: 146-153
        • Aihara T.
        • Morita N.
        • Kamitani N.
        • Kumada H.
        • Ono K.
        • Hiratsuka J.
        • et al.
        BNCT for advanced or recurrent head and neck cancer.
        Appl Radiat Isot. 2014; 88: 12-15
        • Nigg D.W.
        Computational dosimetry and treatment planning considerations for neutron capture therapy.
        J Neuro-Oncol. 2003; 62: 75-86
        • Schmid T.E.
        • Dollinger G.
        • Beisker W.
        • Hable V.
        • Greubel C.
        • Auer S.
        • et al.
        Differences in the kinetics of γ-H2AX fluorescence decay after exposure to low and high LET radiation.
        Int J Radiat Biol. 2010; 86: 682-691
        • Wu X.
        • Chen P.
        • Sonis S.T.
        • Lingen M.W.
        • Berger A.
        • Toback F.G.
        A novel peptide to treat oral mucositis blocks endothelial and epithelial cell apoptosis.
        Int J Radiat Oncol Biol Phys. 2012; 83: e409-e415
        • Alvarez E.
        • Fey E.G.
        • Valax P.
        • Yim Z.
        • Peterson J.D.
        • Mesri M.
        • et al.
        Preclinical characterization of CG53135 (FGF-20) in radiation and concomitant chemotherapy/radiation-induced oral mucositis.
        Clin Cancer Res. 2003; 9: 3454-3461
        • Bortolussi S.
        • Postuma I.
        • Protti N.
        • Provenzano L.
        • Ferrari C.
        • Cansolino L.
        • et al.
        Understanding the potentiality of accelerator based-boron neutron capture therapy for osteosarcoma: dosimetry assessment based on the reported clinical experience.
        Radiat Oncol. 2017; 12: 130
        • González S.J.
        • Casal M.
        • Pereira M.D.
        • Santa Cruz G.A.
        • Carando D.G.
        • Blaumann H.
        • et al.
        Tumor control and normal tissue complications in BNCT treatment of nodular melanoma: a search for predictive quantities.
        Appl Radiat Isot. 2009; 67: S153-S156
        • Kiger W.S.I.
        • Palmer M.R.
        • Zamenhof R.G.
        • Busse P.M.
        Boron uptake by erythrocytes following boronophenylalanine-fructose infusion in humans. IAEA Report KURRI-KR-54.
        2000 (Japan)
        • Imahori Y.
        • Ueda S.
        • Ohmori Y.
        • Kusuki T.
        • Ono K.
        • Fujii R.
        • et al.
        Fluorine-18-labeled fluoroboronophenylalanine PET in patients with glioma.
        J Nucl Med. 1998; 39: 325-333
        • Provenzano L.
        • González S.J.
        BNCT dosimetry tools developed by computational dosimetry and treatment planning department of argentinean BNCT group.