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.
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.
b
* These authors contributed equally
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
Multi-institutional Project
CNEA
Objetive:
Maimónides
University
Roffo Oncologic
Institute
Favaloro
Foundation
Feasibility of ex-situ BNCT for metastatic diffuse lung cancer
Lung is the most frequent metastatic location for many tumours
Metastatic Ewing Sarcoma
Metastatic Wilms Sarcoma
Lung metastases from colon carcinoma
NSCLC Oligometastases
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
Ex-situ BNCT in lung - Workflow
Boronated compound (BPA)
infusion
Surgery
Lung Ablation
RA – 3 Reactor
Lung irradiation
Transport
Surgery
Lung re-implantation
(Autotransplant)
Thermal
Neutrons
Transport
Medical Center
Atomic Center
• “Biological Targeting” non conformational,
• Allow treatment to infiltrating cells, non visible by imaging
techniques and/ or plausible of geometrical delimitation
BNCT
¿Why do this…?
Isolated lung irradiation
Autotransplant
•Avoid healthy tissues (heart, spinal cord,
surrounding the lung
•Maximize the dose to the tumoral volume
lymphatic
nodules,
etc.)
•Avoid compatibility issues associated to regular transplant between donor
and recipient
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
CNEA
Phase I:
Maimónides University
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
16th International Congress on Neutron Capture Therapy
Presented in
Plenary
Biology 1
(June 16th)
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
Stage I/II Clinical
Treatment in patients
Treatment
dosimetric
assessement
Computational
Dosimetry
Dose prescription
and Treatment
planning
Healthy Lung
Irradiation and
radiotolerance study
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
Surgery “Tuning”
BPA
Biodistribution
Dose
Prescription
Dedicated extensions to
maximize lung re-implant
efficiency
Treatment
planning
Treatment
evaluation
Post-surgery critical
cares required
Adequate lung
ablation for
reimplantation
Average ablation surgery duration 80 minutes (from end of infusion)
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
BPA
Biodistribution
Surgery
“Tuning”
Dose
Prescription
Treatment
planning
Treatment
evaluation
Workflow
Biodistribution protocol begins (Boron Kinetics study)
Sampling Pre-infusion (Skin, blood, Urine)
Boron Kinetics study in
healthy adult sheep
Begins I.V. Infusion
BPA
BPA 0,14 M duration 45 min Final dose: 350 mg BPA/Kg
Blood sampling during BPA infusion
End of I.V. infusion
Sampling of several tissues over 5 hours (Blood, Lung, Skin, Urine)
Digestion
H2SO4/HNO3 1:1
1 h 100ºC
End of boron kinetic study
Explanted organ boron distribution study begins
Sonication 90 min.
Boron concentration in
the sheep explanted lung
Right lung ablation
Lung perfusion for preservation during explanted period
Sampling over explanted lung entire volume
[B] microdistribution by
Autoradiography
[B] measured by ICP-OES/ICP-MS
16th International Congress on Neutron Capture Therapy
[10B] ICP-OES or
ICP-MS
Absolute [10B]
[Lung/Blood]
June 14-19, 2014 Helsinki, Finland
Surgery
“Tuning”
BPA Biodistribution
Boron kinetics in healthy
adult sheep
[B] measured data fitted by a twocompartment model (WS Kiger III et al, 2001)
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
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
Surgery “Tuning”
BPA
Biodistribution
Boron Concentration in Explanted lung
after perfusion
Partial Boron washout is expected due to lung perfusion
10
𝑓𝑅 =
𝐵𝑝𝑒𝑟𝑓
Mean retention factor 0.46± 0.03
10
𝐵
16th International Congress on Neutron Capture Therapy
[10B]Lung
[10B]Lung post-perfusion
23.4±0.6 ppm
10.9±0.8 ppm
June 14-19, 2014 Helsinki, Finland
Surgery
“Tuning”
BPA
Biodistribution
Healthy lung dose constraint
(derived from Van Dyk et al. 1981)
Treatment
evaluation
Photon weighted dose
Mean Lung dose <7.5 Gy
10B
Treatment
Planning
Dose prescription
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
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
2.5-3.1
Mesotelioma patient
Suzuki et al (2007)
1.6
Mesotelioma in rats
Suzuki et al (2008)
3
Lung mets in patient
Suzuki et al (2008/2012)
16th International Congress on Neutron Capture Therapy
Inclusion
criteria
T/N ratio ≥ 2
*Early breathing rate end point
JL Kiger et al, 2008
June 14-19, 2014 Helsinki, Finland
Surgery “Tuning”
BPA
Biodistribution
Dose
Prescription
Thermal Column - RA-3 Reactor
Treatment
Planning
Treatment
Evaluation
Lung
Human
collapsed lung
CT scan as
will be treated
MC reconstruction
using MultiCell
algorithm
 Ezeiza Atomic Centre
 Internal air cavity surrounded by
graphite
 Quasi –homogeneous flux (1010 n
cm-2 s-1) from all directions
16th International Congress on Neutron Capture Therapy
Treatment
planning in
MCNP6
June 14-19, 2014 Helsinki, Finland
Surgery
“Tuning”
BPA
Biodistribution
Dose
Prescription
Treatment
Evaluation
Treatment
Planning
Dose distribution in human lung volume
T/N ratio = 3
Mean dose = 7.5 GyW
Clinical scenario
397 sec (~6.5 min)
 Entire volume cannot be tumour
 Limited number of nodules spread in the healthy lung volume
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
Surgery
“Tuning”
BPA
Biodistribution
Dose
Prescription
Treatment
Planning
Treatment
Evaluation
Tumour control probability (TCP) model
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
 Generate 10 tumoral nodules
randomly distributed in the lung
 Repeat the N times
 Derive TCP in each case.
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)
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
Conclusions:

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.
16th International Congress on Neutron Capture Therapy
June 14-19, 2014 Helsinki, Finland
Conclusions (cont.):
 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
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