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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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)
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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)
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
[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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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
Surgery “Tuning”
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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
Surgery “Tuning”
BPA Biodistribution
Dose Prescription
Treatment Planning
Treatment Evaluation
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
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
Tumour control probability (TCP) model
Surgery “Tuning”
BPA Biodistribution
Dose Prescription
Treatment Planning
Treatment Evaluation
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.
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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:
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
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.):
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland
Thank you very much for your time
16th International Congress on Neutron Capture Therapy June 14-19, 2014 Helsinki, Finland