Potential Boron/Gadolinium Neutron Capture Therapy Program at Fermilab

Potential Boron/Gadolinium Neutron Capture Therapy Program at Fermilab

Potential Boron/Gadolinium Neutron Capture Therapy Program at Fermilab James S. Welsh, MS, MD Problems and solutions No clinical BNCT in the USA presently Reactor-based treatments pose some challenges Fermilab accelerator-based approach

might be practical, effective and affordable Basic principles BNCT is a binary treatment modality in which neither component alone is lethal or highly toxic Interaction of a thermal neutron and 10B creates highly biologically effective radiation in-situ Such radiation is capable of dealing with

chemotherapy/radiation-resistant phenotypes irrespective of genetic details MGMT promoter methylation, EGFRvIII , mutant isocitrate dehydrogenase isozymes, 2-hydroxyglutarate, PTEN, ATRX hypoxia/HIF-1 alpha, VEGFR2, etc, etc, etc Success is predicated on selective localization of boron in tumor cells and adequate flux of

neutrons of appropriate energy to the tumor BNCT History Concept proposed shortly after Chadwicks discovery 1934 Goldhaber in Cambridge, England demonstrated that an isotope (10B) had a high avidity for thermal neutrons 1936 Gordon Locher, biophysicist at Bartol Research Institute in Swarthmore, PA

suggested that if tumor could be loaded with 10B and then the region flooded with slow neutrons, a dose-enhancement effect could be achieved (AJR 36:1; 1936) The basic three neutron energies Thermal = 0 0.4eV

Epithermal = 0.4eV 10keV Fast >10keV Neutron interactions Neutron decay Recoiling nuclei (scattering) Nuclear disintegrations Neutron capture Neutron Decay

Nuclear disintegration Spallation 12C + n 3 16O + n 4 Fission: 235U(n,F) 10B(n,)7Li Small

total fraction of absorbed dose but relatively high biological effect because of the high-LET of the fragments Neutron interactions Neutron Capture Cross

sections inversely related to energy (Enrico Fermi 1935) E hhc/ = h/p KE= p2/2m = 2.87 x10-9/(E)0.5 cm Fast neutrons: deBroglie wavelength ~10-12 cm Thermal neutrons: 1.8 x 10-8 Cross sections increase inversely with energy or Slow, fat and fuzzy neutrons hit easier

Neutron Capture Cross sections vary heavily with other variables besides deBroglie wavelength Isotope effects Cd has an absorption cross section of 7000b at 0.176 eV This is due mostly to 113Cd which is only 12.26%

abundant but has a cross section of 20,000 barns Other isotopes also have large cross sections for neutron capture (e.g. 10B, 157Gd) Neutron Capture Neutron capture often leads to Neutron Activation A

= Rk = (FactN) * (1 e-kt)e-kt R = (FactN)/k * (1 e-kt)e-kt Basis for neutron activation analysis to determine presence of trace elements (n,) reaction Many nuclei undergo radiative capture

and emit a prompt capture gamma e.g. 1H (n,) 2H Photon in Emax of 6-10 MeV rough agreement with the neutron binding energy e.g. 157Gd(n,)158Gd releases 7.9 MeV

One or several gamma photons can be emitted (n,) reaction (n,) typically occurs only with fast neutrons Boron

and Lithium are two exceptions 6Li(n,)3H A means of making tritium 10B (~20% natural abundance) has a cross-section of 3990b for thermal

neutrons 10B(n,)7Li Neutron detection instruments - and BNCT! General thermal neutron interactions in tissue during BNCT Hydrogen recoil (proton scattering)

Nitrogen neutron capture Hydrogen neutron capture Boron neutron capture Hydrogen recoil Collisions of nth with hydrogen (protons) Recoiling protons dissipate energy Little energy actually transferred this way But 99% of flux attenuation (of thermal neutrons) is via proton scattering

Nitrogen neutron capture Capture of nth and emission of a 500keV proton 14N(n,p)14C Products have a 10m range of dose deposition

Speculation: Could some of the positive effects of BNCT be due to the increased nitrogen content of aneuploid tumor cells??? N-capture But constitutes 25-50% of non-boron dose little effect on flux attenuation

Together with hydrogen neutron capture >99% of non-boron tissue dose Hydrogen neutron capture Absorption is followed by a 2.2MeV prompt gamma

1H(n,)2H Mean path of gamma photon for dose-deposition is 5-10cm 50%-75% of non-boron dose is due to hydrogen capture As with N capture, has little affect on attenuation of beam Boron neutron capture

10B(n,)7Li 10B + 1n 7Li + 4He + Average of 2.31MeV kinetic energy between the (1.47MeV) and 7Li (0.84MeV) 4He range ~ 7m 7Li range ~ 4 m Initial LET is between 200-300 keV/ m Basic radiobiological principles BNCT

products possess high dE/dx (i.e. LET) High LET reduced OER High-LET radiation typically confers a higher RBE for tumor cell killing More difficult to repair little to no PLDR or SLDR Direct action on biomolecules often cannot be mitigated (whereas indirect action might be via free radical scavengers)

LET LET 60 Co 0.2 150 MeV protons 0.5

250 kVp X-rays 2.0 14 MeV neutrons 100 2.5 MeV alphas 166

Heavy charged particles 100-2000 The ideal LET for cell killing RBE Boron neutron capture 10B is 19.9% naturally abundant

Cross section for thermal neutrons (th) = 3990 barns Requires ~109 10B per cell or 35g 10B/g tissue At this concentration 85% of radiation damage will be due to the BNCT reaction Boron neutron capture Normal tissue ideally should be kept under

5 g/g Tumor cellular concentrations of 20-40 ppm have been achieved With tumor-normal tissue concentration ratios of 3:1 to 10:1 Alternatives to Boron-10 Lithium-6 Good

nuclear properties but difficult chemistry Helium-3 and xenon-135 Higher cross sections than 10B 135Xe has highest measured at 2,720,000 barns! Nobel gases: chemically and biologically useless Additionally 135Xe is radioactive

Uranium-235, Undergo plutonium-241, americium-242 fission into very high LET products 242Am has a cross section of 8000b All are radioactive Alternatives to Boron-10 Cadmium-113 Larger

and Samarium-149 cross sections than boron-10 but result in prompt gammas rather than high-LET hadron fission products But is that a real drawback??? Alternatives to Boron-10 Gadolinium-157 Paramagnetic effects on protons Allows visualization and localization with mm

resolution Many approved Gd-containing MRI contrast agents MRI contrast agents such as gadopentetate dimeglumine (Magnevist), gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) are routinely used Makes the idea attractive one could determine ahead of time if the Gd is accumulating in the tumor or not Gadolinium as a neutron capture

agent? Natural abundance of 157Gd = 15.6% Thermal neutron cross-section 62x 10B th = 255,000 barns Large cross section means self-shielding of deep seated tumors Might require >200 ppm But less than 1000 ppm overall to reduce toxicity

Gadolinium-157 157Gd(n,)158Gd releases 7.94 MeV total kinetic energy over twice that of 10B(n,)7Li Gd + nth [158Gd] 158Gd + + 7.94 MeV 157 How is that energy distributed????

Gadolinium-157 Prompt gammas converted into characteristic xrays as well as: Conversion electrons Auger electrons Coster-Kronig electrons Showers

with submicron ranges in tissue Auger and Coster-Kronig e-s have high LET! But submicron range suggests GdNCT might require intranuclear localization of Gd Highly toxic to work with Gadolinium as a neutron capture agent? Kassis 2005 Auger and Coster-Kronig electrons are short-range and high-LET/high RBE

GADOLINIUM MUST BE IN NUCLEUS FOR REAL BIOLOGICAL EFFECT Perhaps immediately adjacent to the DNA molecules Thermal neutrons Very rapid falloff; HVL = 2cm Negligible skin sparing Useful BNCT treatment depth <4cm depending on [10B] Therefore tumor must be superficial AND

Skin and skull reflected during BNCT treatment(!) Intraoperative radiation therapy Thermal neutrons Wide fields can improve PDD BNCT treatment depth ~6cm at 15-22 cm diameter fields But still requires an intraoperative approach

Heavy water Ordinary hydrogen captures more neutrons than deuterium does Many neutrons lost by H-capture before being able to induce 10B(n,)7Li Replacing body water with D2O can enhance thermal neutron penetration by up to 20-30% Heavy water concentrations up to 30% are not toxic

Epithermal neutrons Better penetration Lose energy via scattering (moderation) to thermal energies HVL 4-5 cm beyond build-up peak 10B does NOT capture epithermal neutrons Thus there is superficial tissue dose sparing An injection of thermal neutrons at depth BOTTOM LINE: No surgical reflection needed!

Allows fractionation Caveats With thermal neutrons recoil protons contribute negligibly to total dose With epithermal (and fast) neutrons, recoil protons contribute significantly Moderation process yields fast recoil protons and

if energy if high enough, carbon and oxygen nuclear reactions Thus high-energy neutrons may be suboptimal if they yield unacceptably high background dose 0.5 30 keV neutrons may be best for non-operative BNCT Generally desirable features Epithermal

neutron beam Flux >2x109cm-2s-1 Treatment < 1hr, preferably <30 minutes <2.8x10-12 Gy cm-2 fast neutrons plus gamma photons contamination Producing appropriate neutrons Nuclear reactors D-T generators

Californium-252 Cyclotrons and linacs Stripping reaction Cyclotrons and linacs Knock-out process Research reactors 100kWth 40MWth 235U fission fast neutrons moderated by tens of cm of D2O then

filtered through cms of Pb or Bi to remove gamma rays Beam hardness (i.e. thermal:non-thermal neutrons) quantified by Au:cd ratio Higher Au:Cd means more thermal enhancement MITR-II Dedicated

medical treatment room Vertically oriented neutron beam (coming from above) Thermal and epithermal fission converter neutron beams Contamination: <1.2x10-13 Gy cm-2 fast neutrons <3.2x10-13 Gy cm-2 Gamma radiation 16cm

diameter field 5x109ns-1cm-2 Nuclear reactors Similar set ups were in existence at Brookhaven National Lab High Flux Reactor in Petten, Netherlands FiR1 in Finland R2-00 research reactor in Studsvik, Sweden

D-T generators 2H + 3H 4He + 1n + 17.6MeV Low E deuterons (100-300 keV) 14.2MeV goes to neutron (monoenergetic) E too low for fast neutron clinical applications Isotropic: Thus low yield in any one direction Low dose-rate (~15 cGy/min) attempts to increase dose-rate by increasing d

current burns up expensive tritium) DD generators are similar to DT generator but doesnt deal with radioactive tritium Isotopic sources: Cf-252 252Cf 248Cm + 4 252Cf fission + 1n

Average of 3.7 neutrons per spontaneous fission Energy range of 0 to 13 MeV Mean value of 2.3 MeV ~1MeV T1/2 = 2.64 years Beam quality equal to reactor-based approaches

Isotopic sources of neutrons 1 g emits 2.3 million n/s Requires ~100 g for adequate flux for BNCT Approximately the entire annual production of Oak Ridge and the Research Institute of Atomic Reactors in Dimitrovgrad, Russia In principle could allow radioisotope driven 235U subcritical multiplying assemblies Reduces needed 252Cf 10-fold

Economics remain to be seen Producing neutrons Cyclotron/linac stripping reactions High-E deuterons (15-50MeV) strike a Be or Li target and are stripped of their protons yielding a neutron beam First suggested by J. Robert Oppenheimer Single

peak in spectrum Average energy 40% of incoming deuteron Producing neutrons Knock-out process Incoming p knocks out a n Broad neutron E spectrum with a higher energy peak than stripping rnxs Low E neutrons must be filtered out to

harden beam for fast neutron clinical use Resultant depth doses comparable to 6MV linac Accelerator approaches In principle cyclotrons or linacs could deliver even higher quality beams than ISRNB, cheaper, hospital based, less security concerns and inherently safer than reactors 7Li(p,n)7Be

Lower energy less moderation needed higher n flux But ~10mA current required which is beyond hospital-based cyclotrons Accelerator approaches Science research Labs (Somerville, MA) compact tandem cascade accelerator design 2.5MeV p+ Li Goal: 4mA beam current

Can be moderated & filtered to an epithermal beam Accelerator approaches 7Li(p,n)7Be has higher flux but has serious limitations Li has a low MP Poor thermal conductivity And the produced 7Be is radioactive

Thus a trade-off on flux is needed: 9Be(p,n)9B Suzuki high yield, higher MP, non-radioactive et al: 2mA 30MeV p+ Be AS-BNCT(KURRI) > KUR-BNCT for deep seated tumors Accelerator approaches

Tanaka et al: 1mA 30MeV p+Be designed for Kyoto Treatment times less than 30min and <12.5GyEq to normal brain tissue Other options include 9Be(d,n)10B stripping rxn 12C(d,n)13N 13C(d,n)14N may be best on paper as far as yield of appropriate E neutrons

Clinical results USA: Epithermal beams; Boron biodistribution studies; 3D MC treatment planning 22 pts on Phase I/II trials; 20 with GBM BPAf via central line

Clinical trials at BNL and MIT 1994 250mg/kg x1hr (n= 10)

300mg/kg x 1.5h (n = 2) 300mg/kg x 2 h (n = 10) Med age = 45 (24-78 yrs) No major side effects - alopecia and scalp dermatitis 76% radiographic regression followed by stability Med OS = 13 mo Clinical results Finland:

Clinical trials at FiR1 18 pts 1999-2001

Epithermal beams BPAf 290 400 mg/kg All had surgery; no chemo; no external beam Avg PTV dose = 30 61 Gy(W) Avg nl brain dose = 3 6 Gy(W) Single fraction with opposed laterals Well tolerated - no deaths in first 6 months (6 mo OS =100%) 1 yr OS = 61% Clinical results Sweden:

Clinical trials at R2-00 Studsvik 30 GBM pts age 26 to 69 yrs in a Phase II trial 26 had surgical debulking Epithermal beams BPAf 6hr infusion of 900 mg/kg Neutron irradiation began 2hrs after end of infusion All had surgery; no chemo; no external beam Avg GTV dose = 15.4 4.3 Gy(W) Avg nl brain dose = 3.2 6.1 Gy(W) 4 had GI effects probably secondary to BPAf Med OS = 14.2 mo

Salvage temozolamide led to 17.7 mo Clinical results Japan: Dr Hiroshi Hatanaka (Tokyo) Began in 1968 at Hitachi Nuclear Reactor BSH (NaB12H11SH)

183 total pts Nakagawa et al (1997): 149 pts; 64 with GBM Thermal neutrons beams 7% GBM pts and 56% AA pts survived > 2 yrs Med OS: GBM = 640 days; AA = 1811 days Range: GBM: 39 8138 days(!); AA: 17 - 6641 days Clinical results

Nakagawa et al (2003): 105 pts treated 1978 97 10 with mixed beams, rest thermal neutrons beams All surgically debulked 2 wks before BNCT 100mg/kg BSH starting 12-13 hrs before BNCT Balloon placed into surgical cavity to maintain size during BNCT Intraoperative approach Min tumor dose = 15 Gy Min target dose = 18 Gy Max vascular dose <15Gy Total gamma radiation dose <10 Gy

Clinical results Nakagawa et al (2003) Results: 5 of 10 GBM pts died Of these five 2 showed local recurrence 3 showed disease elsewhere in brain (dissemination) but no local recurrence on autopsy

Five of the ten were still alive in 2003 (at least five years later, maybe 24yrs?) Clinical results Kawabuta et al (2008) 21 GBM pts 2002 07 Epithermal beams; BSH plus BPA 10 BNCT only: Med OS = 14.1 mo

11 pts with fractionated EBRT boost of 20 to 30 Gy : Med OS = 23.5 months Clinical results Epithermal neutrons Non-surgical approach BSH plus BPA 30 Gy EBRT boost to deepest part Temozolamide on recurrence Med OS = 25 months

Fermilab Neutrons Produced by proton on Be knock-out process 9Be(p,n)9B 66MeV p Be p+(66)Be(49) Max

E ~ 66MeV Mean E = 25 MeV The Spoiler Conclusions

Even in its current iteration, BNCT appears equivalent to current standard treatment (maximal surgical resection, IG-IMRT plus concurrent temozolamide and adjuvant temozolamide) for GBM but in a single session Modernized BNCT (epithermal neutron beams, new nontoxic tumor-localizing boron compounds, 3D treatment planning, in-vivo boron quantitative methods) Possibly fractionated with integrated temozolamide or external beam radiation therapy Could be a very valuable treatment modality for GBM

Could be possible at FNAL

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