BNCT, a binary radiotherapy at cellular level Dr. César Ceballos Sánchez. (CEADEN) Physics and Applications of High Brightness Beams Havana, Cuba, March 28th - April 1st, 2016.

This story will be told backwards.

Boron Neutron Capture Therapy (...and they lived happily ever after.)

Boron Neutron Capture Therapy (BNCT) a) 10B carrier, selectively uptaken in tumor cells Binary Radiotherapy b) Thermal neutrons beam ( En< 0.5 eV) at tumor zone n Nuclei σc(nth)[barns] 10B 3840 1H 0.332 12C 0.0037 14N 1.75 16O 0.0002 7Li 4He 10B 10B(n, 4He) 7Li* 7Li + γ (0.48 MeV) + 2.31 MeV (94%) 10B(n, 4He) 7Li + 2.79 MeV (6%)

Boron-delivery agents - Boron in the tumor ~ 20 - 35 ppm - The tumor-to-normal tissue ratio > 3 - Low toxicity Historically: sodium borocaptate (BSH) p - Borono- phenylalanine (BPA) Current development boron delivery agents + tumour- targeting molecules (peptides, proteins, anti-bodies, nucleosides, sugars, porphyrins and liposomes) optimization of the administration method (nanoscale drug delivery systems using liposomes and nanoparticles)

Φn > 109 cm-2s-1 of "proper" neutron spectrum at patient's entrance Therapeutic beam Φn > 109 cm-2s-1 of "proper" neutron spectrum at patient's entrance Thermal (En < 0.5 eV) Shallow tumor: skin melanoma Epithermal (0.5 eV < En < 10 KeV) Deep-seated: brain tumor (GBM) 90% Primary beam BSA Therapeutic beam (Neutron fluency rate degradation & gamma rays production)

D = wBDB + wn,thDn,th + wn,f Dn,f + Dγ Therapeutic beam D = wBDB + wn,thDn,th + wn,f Dn,f + Dγ 10B(n,α) 14N(n,p)14C 1H(n,n’)1H 1H(n,γ)1H + γ from BSA Mixed radiation field

D = wBDB + wn,thDn,th + wn,f Dn,f + Dγ Therapeutic beam D = wBDB + wn,thDn,th + wn,f Dn,f + Dγ ICRU-63, International Commission on Radiation Units and Measurements, 2000 Soft tissue Soft tissue + 45 ppm 10B Normalized neutron Kerma (Gy.cm-2.n-1) Neutron Energy (MeV) Mixed radiation field

Therapeutic beam It strongly depends on the primary beam - High fluency rate at the "right" energy - As little as possible “contaminants” in the radiation beam - Directed into the tumor bed It strongly depends on the primary beam

Neutron Source (Once upon a time...)

Neutron Source - All reported BNCT irradiations on patients have been performed at nuclear research reactors MITR (USA) VTT-FR1 (Finland) THOR (Taiwan) KURR, JRR-4 (Japan) RA-6 (Argentina) Nuclear Reactors: Source & Doom for BNCT - High neutron intensity - Very expensive facilities - Limited number available for BNCT - Far away from hospitals - Safety regulations - Increasingly unpopular Particle accelerators: The shining knights - Cheaper facilities - Placed inside hospitals - Electric machines - Higher public acceptance - Lower intensity

Accelerator-Based BNCT (told forward) Ion source Proton beam Reflector RFQ accelerator Moderator Proton beam Target BNCT (BSA) . .

Accelerator-Based BNCT Nuclear reaction candidates (...or 7Li vs 9Be) 7Li(p,n)7Be Ep threshold = 1.880 MeV at Ep = 2.3 MeV En,max= 573 keV 9Be(p,n)9B Ep threshold = 2.06 MeV at Ep = 4 MeV En,max= 2.1 MeV Lithium Melting point: 180 oC Thermal cond.: 85 W m-1 K-1 7Be => radioactive Beryllium Melting point: 1287 oC Thermal cond.: 190 W m-1 K-1

Accelerator-Based BNCT Nuclear reaction candidates (...or 7Li vs 9Be) Kreiner et al., Reports of Practical Oncology and Radiotherapy, 21 (2016) 95-101

Accelerator-Based BNCT AB-BNCT Worldide Kreiner et al., Reports of Practical Oncology and Radiotherapy, 21 (2016) 95-101

BNCT recent clinical trials (RB-BNCT) Finland: (2008) Recurrent GBM: - 22 patients previously undergone standard therapy and following recurrence, received BNCT using BPA as the boron delivery agent - Median Survival Time: 7 Months (2011) Recurrent Head and Neck Cancer - 30 patients with inoperable, locally recurrent cancers of the head and neck region - The two-year overall survival was 30% - 27% of the patients had no evidence of recurrent disease at 2 years. Japan: (2008) Recurrent Head and Neck Malignancies (HNM) - 26 patients were treated with BNCT following recurrence of HNM after treatment with standard therapy. It had been considered that there were no other treatment options - BNCT was found to improve QOL - Survival periods after BNCT ranged from 1 to 84 months R L. Moss, Critical review, with an optimistic outlook, on BNCT, ARI, 88 (2014), 2-11

Final Remarks - BNCT involves multidisciplinary collaboration from nuclear physics to surgery, from chemistry to radiation oncology, and from mathematics to radiation biology. - Clinical trials have shown good results on treating recurrent cancers as: GBM, Head and Neck, Lung and Gastrointestinal. - The advancement (and the future) of BNCT requires neutron sources suitable for installation in hospital environments. Particle accelerators are most appropriate for this purpose.

The End

In-air FOM for the therapeutic beam. Limits Φn th(≤ 0.5 eV) ≥ 109 [cm-2 s-1] Φn th/ Φn tot ≥ 0.90 Kn epi+fast / Φn th ≤ 2· 10-13[Gy cm2] Kγ/ Φn th