ex-situ lung bnct at ra-3 reactor: computational dosimetry and boron biodistribution study ex-situ...

Ex-situ lung BNCT at RA-3 Reactor: computational dosimetry and boron

biodistribution study*Farias R.O.a,b , *Garabalino M.A.a , Trivillin V.A. a,b, Ferraris S.c ,Santa María

J.c ,Lange F.c ,,Monti Hughes A. a ,Pozzi E.C.C.a ,Thorp S.a ,Curotto P. a ,Miller M. a ,Santa Cruz G.A.a ,Bortolussi S. d ,Altieri S. d ,Portu A. a,b ,

Saint Martin G.a ,Schwint AE a,b y González S.J. a,b

aComisión Nacional de Energía Atómica (CNEA), Argentina.b Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.

C CIDME, Universidad Maimónides, Argentina.dDipto. di Fisica Nucleare e Teorica (U.Pavia) e Instituto Nazionale di Fisica Nucleare,Italia.

* These authors contributed equally

16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland

Multi-institutional Project

CNEA Maimónides University

Roffo Oncologic Institute

Favaloro Foundation

Objetive: Feasibility of ex-situ BNCT for metastatic diffuse lung cancer

Lung is the most frequent metastatic location for many tumours

Metastatic Ewing SarcomaMetastatic Wilms Sarcoma

Lung metastases from colon carcinomaNSCLC Oligometastases


Ex-situ BNCT in lung - Workflow

Boronated compound (BPA) infusion

RA – 3 ReactorLung irradiation

ThermalNeutrons

Surgery Lung Ablation

Surgery Lung re-implantation

(Autotransplant)

Transport

Transport

Medical Center Atomic Center

¿Why do this…?

• “Biological Targeting” non conformational,• Allow treatment to infiltrating cells, non visible by imaging

techniques and/ or plausible of geometrical delimitationBNCT

•Avoid healthy tissues (heart, spinal cord, lymphatic nodules, etc.) surrounding the lung

•Maximize the dose to the tumoral volumeIsolated lung irradiation

•Avoid compatibility issues associated to regular transplant between donor and recipient Autotransplant


CNEA Maimónides University

Phase I: Pre-clinical studies

Ovine Model (Big Animal Model)• Boron biodistribution• Surgical technique optimization• Healthy lung radiotolerance

Dosimetry & Treatment Planning• Treatment planning for human lung irradiation• 3D dosimetry in the RA-3 reactor

Small Animal Model• In-situ BNCT therapeutic potential

Presented in Plenary

Biology 1 (June 16th)


Surgery “tuning”lung ablation and

re-implantation

Boron kinetics and biodistribution

studies

Boron concentration in lung during the explanted period

To human PatientDose prescription

and Treatment planning

Computational Dosimetry

Treatment dosimetric

assessement

Healthy Lung Irradiation and

radiotolerance study

Stage I/II Clinical Treatment in patients


Average ablation surgery duration 80 minutes (from end of infusion)

Surgery “Tuning” BPA Biodistribution

Dose Prescription

Treatment planning

Treatment evaluation

Adequate lung ablation for reimplantation

Dedicated extensions to maximize lung re-implant efficiency

Post-surgery critical cares required


Workflow

Sampling over explanted lung entire volume

Lung perfusion for preservation during explanted period

Right lung ablation

Explanted organ boron distribution study begins

End of boron kinetic study

Sampling of several tissues over 5 hours (Blood, Lung, Skin, Urine)

End of I.V. infusion

Blood sampling during BPA infusion

Begins I.V. Infusion BPA 0,14 M duration 45 min Final dose: 350 mg BPA/Kg

Sampling Pre-infusion (Skin, blood, Urine)

Biodistribution protocol begins (Boron Kinetics study)

Surgery “Tuning”

BPA Biodistribution

Dose Prescription

Treatment planning

Treatment evaluation

BPA

Absolute [10B] [Lung/Blood]

[10B] ICP-OES or ICP-MS

Sonication 90 min.

Digestion H2SO4/HNO3 1:1

1 h 100ºC

[B] measured by ICP-OES/ICP-MS [B] microdistribution by Autoradiography

Boron Kinetics study in healthy adult sheep

Boron concentration in the sheep explanted lung


1. Big animal model validated as pre-clinical model in terms of biodistribution. 2. Boron distribution homogeneous in both lung volumes.3. Lung to Blood ratio remain constant at 1.2±0.7 from t=120 min

Surgery “Tuning” BPA Biodistribution

Boron kinetics in healthy adult sheep

[B] measured data fitted by a two-compartment model (WS Kiger III et al, 2001)


[10B]Lung [10B]Lung post-perfusion

23.4±0.6 ppm 10.9±0.8 ppm

Mean retention factor 0.46± 0.03𝑓 𝑅=

[ 𝐵𝑝𝑒𝑟𝑓❑10 ]

[ 𝐵❑10 ]

Surgery “Tuning”BPA

BiodistributionBoron Concentration in Explanted lung

after perfusion

Partial Boron washout is expected due to lung perfusion


10B tumour to normal tissue ratio (T/N ratio)

Reference T/N ratio

Trivillin et al (2013) 1.9 Colon ca. Mets in rat

Bortolussi et al (2011) >3 Colon ca. Mets in rat

Suzuki et al (2008/2012) 2.5-3.1 Mesotelioma patient

Suzuki et al (2007) 1.6 Mesotelioma in rats

Suzuki et al (2008) 3 Lung mets in patient


BPA Biodistribution Dose prescription Treatment

PlanningTreatment evaluation

CBE/RBE Lung Tumour

10B(n,α)7Li 1.4(*) 3.8

14N(n,p)14C 3.2 3.2

Fast neutrons 3.2 3.2

γ-rays 1 1

Mean Lung dose <7.5 Gy (derived from Van Dyk et al. 1981)

Healthy lung dose constraint Photon weighted dose

Inclusion criteria

T/N ratio ≥ 2

*Early breathing rate end point JL Kiger et al, 2008


Surgery “Tuning”BPA

BiodistributionDose

PrescriptionTreatment Planning

Treatment Evaluation

Ezeiza Atomic Centre Internal air cavity surrounded by

graphite Quasi –homogeneous flux (1010 n

cm-2 s-1) from all directions

Thermal Column - RA-3 Reactor

MC reconstruction using MultiCell

algorithm

Treatment planning in

MCNP6

Human collapsed

lung

CT scan as will be treated

Lung



BPA Biodistribution

Dose Prescription

Treatment Planning


Dose distribution in human lung volume

397 sec (~6.5 min)Clinical scenario

Entire volume cannot be tumour Limited number of nodules spread in the healthy lung volume

Mean dose = 7.5 GyW

T/N ratio = 3


Tumour control probability (TCP) model


BPA Biodistribution

Dose Prescription

Treatment Planning


We chose a TCP model used in photon fractionated RT (Martel et al 1999)

Find RT equivalent doses in a hypo-fractionated scheme (BNCT, SBRT) using a survival model

Adjust the survival model (modified Hugh- Kellerer) from experimental data in cells (H460 – NSCLC)

Apply the adjusted survival model to the TCP model

Verify the results! (compare TCPs obtained with the model versus the reported in SBRT)

Generate 10 tumoral nodules randomly distributed in the lung

Repeat the N times Derive TCP in each case.


Big animal model validated as pre-clinical model in terms of

biodistribution.

Blood, Lung and Skin boron concentration are qualitatively and

quantitatively equivalent to human.

Boron distribution is homogeneous in the lung volume. Valid for

both lungs.

After perfusion, explanted lung boron concentration was

determined and average retention factor calculated.

Conclusions:


Treatment planning was simulated for human lung in the RA-3 reactor considering published lung dose prescription and T/N ratios,

Irradiation duration is lower than 10 minutes. Promising doses are achievable for T/N ratios higher than 2. An average number of controlled nodules higher than 0.8 is

expected when a dedicated TCP model is applied.

A feasible and promising treatment technique is being developed for lung metastatic nodular tumours.

Eleven experiences were performed in the last 2 years.

7 Autotransplant surgery “tuning”,

3 biodistribution studies,

1 Autotransplant surgery with Irradiation

Conclusions (cont.):


Thank you very much for your time


ex-situ lung bnct at ra-3 reactor: computational dosimetry and boron biodistribution study ex-situ...

Documents

human lung irradiation

surgery tuning lung

lung workflow administracin

d dosimetry

finland slide

international congress

neutron capture therapy

reimplantation boron