10B CONCENTRATION ANALYSIS

IN PRIMARY HUMAN LUNG ADENOCARCINOMA

BY THERMAL CAVITY OF PHONES PHOTO-NEUTRON CONVERTER

Canditato: Relatore:

Katia Alikaniotis Dott.ssa Alba Zanini

Torino, 5 ottobre 2009

OUTLINE

What’s BNCT?

Neutron Source

Photoneutron production from Medical Linac

PhoNeS: Feasibility study results

PhoNeS: Portable prototype design and manufacturing

First biological trials

Lung carcinoma study

Activation study

Boron Concentration

Conclusion

Work in progress

BNCT (BORON NEUTRON CAPTURE THERAPY)

Nuclear reaction:

BNCT is a higlt selective therapy which use the hight absortion cross section ofthe thermal neutron on 10B.It is a “Binary Therapy” which consist in:

1. Subministre a boral compost, the BPA (BoronPhenilAlanina)2. Irradiation of biological sample by thermal neutron

MeV) (0,48 MeV) (1,47 MeV) Li(0,84 *B B n 71110

th

BNCT (BORON NEUTRON CAPTURE THERAPY)

Advantages:• hight corss section of low energy neutron (3840 barn a 0.025 eV);• positive Q-value (Q = 2.792 MeV);• reaction product range is comparable to cell dimensions (9um);• radiation dose is delivered only during the neutron irradiation of the tissue• reaction product are not radioactive

More is boron concentration in tumoral

tissue than the healthy one higher is the therapy

selectivity

T = CT / CH

Scheme of boron fission reaction in the cell

Different boron concentration in tumoral and healthy cell

NEUTRON SOURCENuclear Reactors are at the moment the only neutron source for BNCT research

E < 0.4 eV THERMAL0.4 eV < E < 10 keV EPITHERMAL

E >10 keV FAST

A neutron source is suitable for BNCT if the neutron beam submit to IAEA (InternationalAtomic Energy Agency) parameters, IN AIR FREE BEAM PARAMETER, that define theminimum necessary neutron flux and the maximun indesiderate dose due to radiationand fast neutron.

Thermal neutron flux:

Fth > 108 n cm-2 s-1

Reduce neutron fast and component:

Gy cm2

1310FTh

FastDGy cm2

1310FTh

D10-3

10-2

10-1

100

101

102

103

104

0,0

2,0x1012

4,0x1012

6,0x1012

8,0x1012

1,0x1013

THERMAL

7.00E+11 n/cm2/s

EPHITERMAL

3.90E+10 n/cm2/s

flusso totale 1.15E+12 n/cm2

Spettro Termico in scala logaritmica

(n/c

m2/s

)

Energy (MeV)

“Conventional BNCT is inefficient because atomic reactor is used for neutron source. In this study, we demonstrated accelerator – based BNCT using new boron agents.” from the World Conference of Munich, 2009

PHONES PROJECT

Main goals

A novel approach to BNCT based on photoneutron production with

high energy (18 – 25 MV) radiotherapy linear accelerators

•By using a suitable photoconverter installed at the accelerator head it is possible to:

• increase the photoneutron production;

• maximize the therapeutic neutron component (E < 10 keV)

• minimize the fast neutron and γundesired dose

PhoNeS project is devoted to design and

manufacture an in-hospital BNCT facility

PHONES PROJECT

• Simple prototype easy to be transport and installat at the existing medical linac head

BNCT treatments inside a radiotherapy hospital department (Medical care, Hospitalization, Combined therapy)

Transportable Prototype

Optimized Prototype and Dedicated Linac

• Different kinds of optimized moderating structures:

thermal, epithermal or mixed beams according to the medical need.

• Suitable facility for in-hospital BNCT research and experiments on cells and biological samples

In the future

Advantages

Threshold Energy G.D.R.

W: 7.42 MeV Fe: 10.9 MeV

Cu: 9 MeV Pb: 7.41 MeV

Neutrons are produced by Giant Dipole Resonance (G.D.R.) reaction

700keV <En< 1 MeV

PHOTONEUTRON PRODUCTION IN LINACS

LINAC HEADNeutrons

Gamma beam

186W: Cross-section 450 mbarn at 13,5 MeV

LINAC PHOTONEUTRON PRODUCTION MECHANISM

Electrons

Linac Target X-ray emission by Bremsstrahlung

GDR Giant Dipole Resonance

on High Z material

photonsPb

neutrons

THERMAL EPITHERMAL FAST

THERMAL EPITHERMAL FAST

Mean Neutron Energy:

700keV <En< 1 MeV

Neutrons have to be reduced in energy less than 10 keV for BNCT

applications

SIMULATION METHOD:MONTECARLO MCNP4B-GN SIMULATION CODE

Evaporative component

Isotropic angular distribution at lower energy

Maxwellian neutron energy distribution

Direct neutron knockout component

Anisotropy spatial distribution: f(θ) = a + bSin2θ

Energy distribution: En = Eg - Es

The simulation code MCNPGN (NEA-1733), especially developed for (g,n)photoproduction in linac accelerators (by INFN Turin), has been used to treatthe electromagnetic cascade and the photoneutron production and transport.

Both (g,n) and (g,2n) channels are treated

INSTRUMENTATION

Neutron Bubble Detector: BDT, BD−PND

• Accuracy: 20%• No sensitivity to g radiation• Isotropic angular responce• Large dose range detection• Handiness to use

BDT Thermal Neutron (E<0.4 eV)

BD−PND Fast Neutron (100keV < En < 20MeV)

BDS6 threshold neutron detector (10, 100, 600, 1000, 2500 and 10000 keV to 20 MeV)

Gamma Detector: EBT GAFChromic films• Indipendent energy response (from 50keV to 20MeV)

• Equivalent Tissue compisition

• Saturation at 5Gy

• Accuracy ± 5%

• Self-acquire

• Reading dose by Scanner

PHONES PROJECT: FEASIBILITY STUDY

1° 2° 3°

OPTIMIZED

4°

TUNGSTEN

(PHOTOCONVERTER)

GRAPHITE

(MODERATOR)

LEAD

(GAMMA SHIELDING)

PMMA

(MODERATOR)

BISMUTO

(REFLECTOR)

POLYETHILENE

(MODERATOR)

•Accurate analysis of (g,n) and neutroninteraction cross-section (ENDF/B-VI)

•An optimized geometrical configuration ofthe various components has been designed.

•The high-Z core for neutron production andthe low-Z moderating structures are suitablyshaped.

PHONES PROJECT: FEASIBILITY STUDY

BEFORE PhoNeS facility

10-9

10-7

10-5

10-3

10-1

101

0,0

1,0x10-8

2,0x10-8

3,0x10-8

4,0x10-8

5,0x10-8

Energy (MeV)

Configurazione 4 ottimizzata

Configurazione 3

Confronto configurazioni

Configurazione 2

Neu

tro

n F

luen

ce R

ate

(cm

2/e

- )

Configurazione 1Configuration 1

Configuration 2

Configuration 3

Configuration 4

(OPTIMIZED)

AFTER PhoNeS facility

Thermal neutron flux

(cm-2s-1)

1 3.02E6

2 2.28E7

3 3.36E7

4 1.06E8

In the optimized configuration an improvement of more than one order of magnitude for the thermal neutron fluence rate is observed.

PORTABLE PHOTOCONVERTER DESIGN AND MANUFACTURING

Photoconverter:

-Photoneutron (γ,n) production by risonanza gigante dipolo tramite High Z elements : Lead, Tungsten

W - Tungsten

Moderator:

-Photoneutron slowing down until to thermal energy-Minimizing fast neutron component

Carbon, D2O, Polyethylene- Low Z elements and hydrogenase:

C - Carbon

Gamma shielding and neutron reflector

-Minimizing gamma component and neutron collimation

(Lead ).

Pb - Lead

PHONES BIANCO: PROTOTYPE FOR BIOLOGICAL BNCT TRIALS

50% boron carbide slabs

50% Epoxy resin slabs, thickness 2 mm

Lead slabs, thickness 1 mm

Graphite:

- 2 horizontal blocks, 15 x 30 x 60 cm3

- 2 vertical blocks, 15 x 30 x 30 cm3

60 cm

60 cm

Closed cavity configuration

• Two carbon fibre boxes filled with heavy water and a polyethylene slab to close

Thermal neutron field of suitable intensity and energy spectral distribution for biological samples irradiation

C C

Pb

D2O

POLYETHILENE

Cavity: 20 x 20 x 10 cm3

CLOSED CAVITY CHARACTERIZATION

Thermal Neutron

(96

,17

±1

9,2

3)

μSv

/s

(94

,86

±1

8,9

7)

μSv/s

(97,12 ± 19,47) μSv/s

(98,32 ± 19,66) μSv/s

Thermal neutron dose distribution inside the closed cavity

(BDT detector)

Thermal neutron dose distribution insidethe closed cavity

(BAS-ND Gd2O3 Imaging Plate)

Average Neutron Components

Fluence Rate

(n cm-2)

Dose

(uSv s-1)Percentage

Thermal + Epithermal (1,2 ± 0.2)E7 (96,6 ± 19,3) 96%

Fast (4,1 ± 0,8)E5 (41,4 ± 8,2) 4%

CLOSED CAVITY CHARACTERIZATION

Thermal Neutron

(96

,17

±1

9,2

3)

μSv

/s

(94

,86

±1

8,9

7)

μSv/s

(97,12 ± 19,47) μSv/s

(98,32 ± 19,66) μSv/s

Thermal neutron dose distribution inside the closed cavity

(BDT detector)

Thermal neutron dose distribution inside the closed

cavity (BAS-ND Gd2O3 Imaging Plate)

Average Neutron Components

Fluence Rate

(cm-2 s-1)

Dose

(uSv s-1)Percentage

Thermal + Epithermal (1,2 ± 0.2)E7 (96,6 ± 19,3) 96 %

Fast (4,1 ± 0,8)E5 (41,4 ± 8,2) 4 %

RESEARCH ON BIOLOGICAL TRIALS

An innovative approach In-Hospital Neutron source

High Energy Linac + PHoNeS photoconverter

Tumor studied To use organs affected by tumours resected from human body in patients surgically treated following the “gold standard”*

BPA uptake method To keep alive the resected organs in extracorporeal circulation during BPA perfusion

To integrate/compare the animal model

To evaluate the CT/CH in human tissue by CR-39 tracks detector

To study the B10 carrier uptake directly in human model

*after informed consent in accordance with the regulations of the institutional review board

Aim of the work

BPA perfusion

• BPA dose subministred to pulmonary lobe was 300 mg/kg tissue

• The BPA solution (0.14 M) was prepared combining BPA with 10% molarexcess of fructose in water. The pH was adjusted to 9.5-10 with NaOH.

• The mixture was stirred and after some minutes pH was readjusted to7.4 with HCL.

Patient # Lobe Weight (g)

BPA somministred(mg)

Perfusion time (hrs)

1 172 150 2

2 166 150 2

3 480 356 4

EX VIVO BPA PREPARATION AND PERFUSION

BPA preparation

artery

Inferior vena

Bronchial tube

SAMPLE PREPARATION

Histological

CR-39

Healthy TumorPeritumoural

After the BPA perfusion samples of normal, peritumoral and tumoral tissue are prepared using Leica Cryostat.

Layers of 10 um thick are deposited on glass for morphological analysis and on CR 39 track detectors for neutron irradiation.

THE CR-39 TRACK-ETCH DETECTORS• Clear plastic (Polyallyl diglycol carbonate (PADC)) sensitive to tracks

of highly ionizing particles such as alpha or 7Li from neutron capture on 10B

• Rectangular shape (37x13x1 mm3); Density 1.30 gcm-3

CR - 39

The CR-39 calibrationAn absolute calibration was performed at TRIGA MARK IIreactor (Pavia) by:

• using a known 10B content thin (25mm) BC-454 10% natural boron

• exposing CR-39 to a neutron fluence of (1.70±0.17)E7 ncm-2

resulting in (7.8±1.4)E-4 tracks/neutron

Relative calibrations to compare with Bubble neutron detectors (BDT, BDS)

good agreement within 10-20%

neutron

tracks

cmneutronsmm

tracks 4

27210)4.18.7(

10)17.070.1(56.1

)20212(

So we can measure 10B concentration

Conversion Factor

EXPERIMENTAL SET-UP FOR BIOLOGICAL TRIALS

e-Linac Elekta 25 MeV max dose rate 400 UM/min

PhoNeS Bianco (weight ~ 400 kg – assembling time ~ h 1.0 )

Thermal neutron fluence rate ~ 1E7 n cm-2s-1

A specific CR-39 calibration was performed before installing the samples in the cavity (with 2000 MU)

UM total: 70000; Total fluence: ~ 1E11 n cm-2; Irradiation Time: ~ 3 hrs

Biologiacl samples: primary lung carcinoma

BIOLOGICAL SAMPLES INSIDE THE CAVITY

PORTABLE PHOTOCONVERTER: ACTIVATION STUDY

Bunker Elekta Precise 25 MV – Hospital Molinette – dose measures

1

2

34

0 POSITIONS

0) Control Room

1) Beginning hall

2) Middle hall

3) Corner

4) Bed

Position Dose (uSv/h) Hour Δt after irradiation

0 0,03 17:26 3600 s

1 0,80 17:27 3660 s

2 0,91 17:28 3720 s

3 6,0 17:29 3780 s

4 11,24 18:48 8520 s

4 11,12 18:53 8820 s

4 10,75 18:58 9120 s

4 10,45 19:03 9420 s

4 10,25 19:08 9720 s

4 10,25 19:13 10020 s

4 10,16 19:18 10320 s

4 9,87 19:23 10620 s

4 9,51 19:28 10920 s

4 9,64 19:33 11220 s

4 1,56 8:38 58320 s

4 1,57 8:43 58620 s

4 1,40 8:48 58920 s

4 1,34 8:53 59220 s

No radioprotection problems inside and

outside the Linac irradiation bunker

0

2

4

6

8

10

12

0 20000 40000 60000 80000

Dose [uSv/h]

t [s]

Decaying curve

position 4 y=15,29*e^(-4*10^-4)x

CR-39 CHEMICAL ETCHING

• After the exposure the CR39 layerswere chemically etched for 2 hrs inNaOH (6N) at 90°C

• 10 um diameter holes correspondingto alpha and 7Li are observed withdensities of the order of 1-2 x 103 mm-2

• Reproducing the features ofthe tissues deposited on thedetectors

CR-39 ANALYSIS

• Image-Pro-Plus © program used formeasuring hole density and sizedistribution.

• Specific sideways illuminationprocedure allow to record highresolution images for comparisonwith histological ones to determine10B concentration in the tissue

BORON-10 CONCENTRATION RESULTS

Healthy Tissue Tumoral Tissue

Histological Corresponding image of sample after irradiation

Histological Corresponding image of sample after irradiation

B-10 Distributionin rat lung tissue

Human Mesothelioma

Human LungAdenocarcinoma

J.L.KigerPhD Thesis,

2006

M. Suzuki,2006

M. Suzuki,2008

PhoNeS 1st patient

PhoNeS2nd patient

PhoNeS3rd patient

PhoNeS3rd patient

(*)

Healthy Tissue (ppm)

10B =15 10B =20.7 10B =17 10B =29±3 10B =28±3 10B =25±3 10B =21±3

Tumour Tissue (ppm)

10B =52.5 10B =27.2 10B =51 10B =40±3 10B =42±3 10B =47±3 10B =63±3

CT/CH

3.5 (after 3h)

1.3 (after

30 min)

3.0(after 3h)

1.4 (after 2h)

1.5 (after 2h)

1.7(after 4h)

3.0 (after 4h)

(*) very preliminar result

by local 10Bdensitometry distribution

BORON-10 CONCENTRATION RESULTS

Kinetic curve of 10B up-take inblood samples during the perfusionof non-small cell lung cancer (lobe#3) with BPA-F solution. ICP-MSdeterminations. The results arereported as mean values of tworeplicates of each sample.

From this preliminary result it isevident that the major concentrationof 10B is reached after about 1,5 hourof perfusion.

0.000

0.020

0.040

0.060

healthy tissue cancer tissue

10B /mg

10B content in healthy and tumour tissues ofnon-small cell lung cancer (lobe #3). ICP-MSdeterminations. The results are reported asmean value of two replicates for each sample.

The 10B content in the healthy tissue is clearlylower to that in the cancer cells and the valuesobtained for the two samples here consideredare 0.019(1) mg and 0.050(2) mg respectively,so the tumour to healthy tissue ratio is∼3 ingood agreement with the value determinatedby neutron authoradiografy after irradiation.

0,0

30,0

60,0

90,0

120,0

150,0

0 60 120 180 240

ug

B1

0 /m

L b

lood

Time (min)

Up-Take curve

ICP-MS Pavia

Como analysis

CONCLUSIONS

PhoNeS closed cavity provides:

• 1.1E7 cm-2s-1 thermal neutron fluence rate

• spectrum comparable in shape to the neutrons from a nuclear reactor

• an uniform distribution of thermal neutron field

PhoNeS closed cavity representsthe first in-hospital neutron source for:

• cells or biological samples irradiation

• the behaviour of different 10B carriers analysis .

First biological trials

• Evaluation of 10B concentration in tumor and healthy tissuefor human primary adenocarcinoma with ex-vivo perfusiontechnique of resected lobe (3h irradiation time)

WORK IN PROGRESS

Color densitometry

Development of a Realtime system for themeasurement of neutron dose and theconcentration of boron during irradiation

Dedicated Linac

Design and manufacturing of a new PhoNeS cavity

green > 20 ppmblue > 40 ppmorange > 60 ppmred > 80 ppm

Preliminary local 10B distribution on peritumoral biologicalsamples based on a color-densitometry is performed

It is possible to observe areas of different 10B concentrationranging from 98 ppm (tumor tissue) to 21 ppm (healthy tissue)

FINE

Ringraziamenti a:

Alba Zanini

Oscar Borla

Patrizia Chiari

Katia Alikaniotis

Vi ringrazio per l’ascolto

COLLABORATION

Università degli Studi di Torino Università degli Studi di Trieste Università dell’ Insubria di Como Università degli Studi di Pavia IRCC Candiolo (Torino) ASO Ordine Mauriziano (Torino) AOU San Luigi – Orbassano (Torino) AOU San Giovanni Battista (Torino) ASO Sant’Anna (Como) Ospedale Maggiore (Trieste) ST. JOHANNS HOSPITAL Salisburgo (AUSTRIA) GIO’ MARCO s.p.a. MOGLIANO VENETO (Treviso)

APPENDICE A:

RISONANZA GIGANTE DI DIPOLO

E’ un processo a soglia: la soglia varia tra 6 e 18 MeV

L’onda elettromagnetica colpisce un nucleo

induce un’ oscillazione collettiva di tutti i protoni che possono entrare in risonanza con il fotone

questo moto può essere accompagnato dall’ emissione di uno o più nucleoni:

• NUCLEI LEGGERI: prevale emissione di protoni

• NUCLEI INTERMEDI: competizione tra emissione di protoni e di neutroni

• NUCLEI PESANTI: prevale emissione di neutroni (la barriera coulombiana inibisce l’emissione di particelle cariche)

APPENDICE B:

I RIVELATORI A TRACCE

I rivelatori a tracce sfruttano il potere ionizzante della particelle cariche.

Particelle pesanti ad elevata energia (es: a) passano attraverso un materiale dielettrico.

Trasferiscono una frazione di energia per unità di percorso danneggiando le molecole lungo la loro traiettoria.

Dimensioni dell’ ordine dei nanometri.

Attacco chimico con soluzione corrosiva per rendere visibili le tracce.

GAFCHROMIC ETB FILM CHARACTERIZATION

INSIDE PHONES CAVITY

Characterization in view to test the response of GAFChormic in a mixed (neutron-gamma) radiation field

10000 20000 30000 40000 50000 60000 70000

0

1

2

3

4

5

6

7

8

9

10 GAF CALIBARTION

Do

se (

Gy)

UM (Unità Monitor)

IONIZATION CHAMBER (515 cm3)

GAFChromic EBT film

The expected results have been measured before with a 515 cm3

ionization chamber

Good agreement of GAFChromic ETB film until to 5 Gy (saturation level)

CLOSED CAVITY CHARACTERIZATION: GAMMA COMPONENT

THERMAL FAST GAMMA

0,0

2,0x106

4,0x106

6,0x106

8,0x106

1,0x107

1,2x107

1,4x107

Neu

tro

n F

luen

ce R

ate

(cm

-2s

-1)

MCNP-GN SIMULATION

EXPERIMENTAL RESULTS

0,0

2,0x10-4

4,0x10-4

6,0x10-4

8,0x10-4

1,0x10-3

1,2x10-3

1,4x10-3

Do

se G

amm

a (G

y/s)

MCNP-GN Simulation compared with experimental results (neutron and gamma components)

NEUTRONI

Flusso

Sperimentale

(ncm-2

s-1

)

Flusso

Simulazione

(ncm-2

s-1

)

THERMAL (9,7 ± 1,9)E6 (9,8 ± 0,9)E6

FAST (4,1 ± 0,8)E5 (5,9 ± 0,5)E5

GAMMA

Dose

Sperimentale

Gy/s

Dose

Simulazione

Gy/s

(7,03 ± 0,70)E-4 (5,04 ± 0,51)E-4

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

101

0,0

5,0x106

1,0x107

1,5x107

2,0x107

2,5x107

3,0x107

3,5x107

4,0x107

Phones Bianco Gamma Fluence Rate

Ga

mm

a F

lue

nce

Ra

te (

cm-2s-1

)

Energy (MeV)

Low energy gamma component from linac head

CLOSED CAVITY CHARACTERIZATION: PB IN CAVITY

10-8

10-7

10-6

10-5

10-4

10-3

10-2

10-1

100

101

0,0

5,0x106

1,0x107

1,5x107

2,0x107

2,5x107

3,0x107

3,5x107

4,0x107

Phones Bianco no Lead

Phones Bianco - 2mm Pb in cavity

Gam

ma

Flue

nce

Rat

e (c

m-2

e-1

)

Energy (MeV)

Experimental

Fluence Rate

(cm-2s-1)

MCNP-GN

Fluence Rate

(cm-2s-1)

Thermal (1.2 0.2)E6 (9.8 0.9)E6

Fast (4.1 0.8)E5 (4.5 0.5)E5

Experimental

Dose (Gy/s)

MCNP-GN

Dose (Gy/s)

Gamma (no Pb) (7.03 0.70)E-4 (5.04 0.51)E-4

Gamma

(2mm Pb)(1.57 0.15)E-4 (1.04 0.10)E-4

2 mm of Lead in cavity

Gamma dose 5 times lower

No evident difference in

Thermal neutron

Fluence Rate

PHONES “BIANCO” PROTOTYPE: ASSEMBLING

First In-Hospital neutron source for BNCT trials

Polyethylene and B4C slabs Graphite blocks Lead photoconverter and shielding

Heavy Water Carbon Boxes Polyethylene slab Final configuration

Dimension: 60x75x30 cm3 – Weight ~ 400 kg – Assembling time ~ 1.0 hrs

Human lung resected pulmonary lobe affected by non-small cell lung cancer

perfusion with 10B (99%enriched) boronophenylalanine (10BPA)

tissue samples, ~ 10um thickness , ~ 1cm2 area, within two CR-39 layers

artery

Inferior vena

Bronchial tube