Treatment Planning for Boron Neutron
Capture Therapy at the New England Medical
Institute of
Center--Massachusetts
Technology
by
Daniel Katz
Massachusetts Institute of Technology
S.B., Physics, 1994
Submitted to the Department of
Nuclear Engineering
in Partial Fulfillment of the Requirements
for the Degree of
Master of Science in Nuclear Engineering
at the
Massachusetts Institute of Technology
February
1996
© 1996 Massachusetts Institute of Technology
All rights reserved
Signature of Author........
Department of Nuclear Engineering
January 19, 1996
Certified by...
Robert G. Zamenhof
Professor of Medical Physics, Tufts University Medical School
Thesis Supervisor
Certified by..
NJ
Otto K. Harling
Professor of Nuclear Engineering
Thesis Reader
Accepted by...........
OCF TECQNOLOGY
APR 221996
LIBRARIES
Allan F. Henry
I
" ;
Chairman, Department Committee on Graduate Students
a I
1
Treatment
at the
Planning for Boron Neutron Capture Therapy
New England Medical Center-Massachusetts
Institute of Technology
by
Daniel Katz
Submitted to the Department of Nuclear Engineering
on January 31, 1996 in partial fulfillment of the
requirements for the degree of
Master of Science in Nuclear Engineering
ABSTRACT
The aim of this work is the development of an improved treatment
planning software for the Boron Neutron Capture Therapy trials at the
New England Medical Center--Massachusetts Institute of Technology joint
program and to facilitate future operation of the treatment planning
procedure.
A detailed documentation of every step in the treatment
planning procedure, starting with CT scans and leading to RBE-dose
isocontours, is presented in the first part of the thesis. Several treatment
plans of subjects irradiated as part of the phase-I boron neutron capture
therapy dose-escalation melanoma protocols have been prepared by the
author and are presented as examples. The second part of the thesis
focuses on the beam monitoring software, integrating the results that are
obtained from the Monte Carlo-based treatment planning code NCTPLAN
into its operation.
Thesis Supervisor: Robert G. Zamenhof
Title: Professor of Medical Physics, Tufts University Medical School
Thesis Reader: Otto K. Harling
Title: Professor of Nuclear Engineering
Acknowledgments
_____
__
_______________
__
__
__
______
I would like to thank the multitude of people who have helped me and
supported me throughout the past year and a half at MIT. This thesis
work would not have been possible if it wasn't for them.
First, and foremost, I would like to thank Dr. Robert Zamenhof for
supervising my work on this project. He patience and understanding
never ceased to amaze me.
I also would like to thank Professor Otto Harling for reading my thesis in
such a short notice and for just being there and pushing me to do better.
I will never forget his cute holiday cards, decorated with the pictures of
his grandchildren.
Special thanks go to Dr. Guido Solares for his help with anything and
everything relating to my work, from help with using the Mac to help with
personal problems.
Also, thanks to the other members of the BNCT group that have helped me
both as friends and colleagues. In particular, Stead Kiger, Kent Riley, and
Sam Yam.
Lastly, I would like to thank my numerous friends whose moral support
throughout the years will always be special to me.
This research has been supported principally by U.S. Department of Energy
Grant No. DE-FG02-87ER6060.
Table
of
Contents
2
A b stract .............................................................................................................................................
A cknow ledgm ents ..............................................................................
.....................................
T able of Contents ....................................................................................................
...........
4
L ist of Figures ............................................................................................................
.........
6
L ist of T ables ............................................................................................................
...........
8
1
Chapter
Introduction
[1.1] B ackground .......................................................................................................
[1.2] A Brief Review of Boron Neutron Capture Therapy Dosimetry ........
[1.3] A Description of the Beam Monitoring System at MITR-II ................
[1.4] An Outline of the Steps Involved in a BNCT Treatment Plan ..........
[1.5] Thesis Objectives and Outline ....................................... .....................................
Chapter 2
[2.1]
[2.2]
[2.3]
[2.4]
[2 .5]
Procedures
20
Extracting Images from the CT Scanners .........................................
23
Importing Images to the VAX Computer .........................................
.......... 25
Extracting Tissue/Bone Boundaries .......................................
Preparations for MCNP Dose Computations .......................................
29
S cript F iles ................................................................................................................ 30
Chapter 3
[3.1]
[3.2]
[3.3]
[3.4]
[3.5]
Operational
9
11
14
15
18
NCTPLAN
B ackground ............................................................................................................... 34
MCNP Dose Computations ....................................................... 34
37
Program Architecture ..........................................................
NCTPLAN Results and validations ........................................
........... 42
Sample Treatment Plans of Human Subjects .......................................
60
Chapter 4
Beam
Monitoring System
........... 93
[4.1] Description of the Existing System .......................................
96
[4.2] Software Implementation ........................................................................
99
........
[4.2.1] BNCTDose - Purpose and Use ......................................
[4.2.2] LabV IEW 2@ ..................................................................... ................. 100
[4.3] Integration of NCTPLAN results and BNCTDose into the Beam .........
Montioring Software LabVIEW 2 ................................................. 101
Chapter 5
Summary
and
Conclusions
[5 .1] S umm ary .................................................................................................................
[5.2] Recommendations for Future Work .....................................
107
107
List of Figures
Chapter 1
1.1
1.2
1.3
Introduction
Dose rate vs. Depth in human head phantom ............................... 13
16
Schematic of the flow of information in a treatment plan ......
18
Sample tumor isodose contours for a transverse plane ...........
Chapter 3
NCTPLAN
Transverse CT image with the corresponding materials file .... 35
3.1
3.2
Diagram of acrylic shell water-filled head phantom ................. 43
............. 45
3.3 Thermal neutron dose rate ........................................
........... 46
3.4 Epithermal neutron dose rate .......................................
10
3.5
B dose rate ........................................... ................................................. 47
3.6 Total gamma dose rate ..................................... ...................... 48
. 49
3.7 Total dose rate for normal brain tissue ....................................
Transverse normal brain isodose contours ................................... 53
3.8
3.9 Transverse tumor brain isodose contours ..................................... 54
3.10 Coronal normal brain isodose contours ..................................... . 55
3.11 Same as Fig. 3.9 with a midline tumor pasted ............................ 56
3.12 Gain Factor vs. 10 B concentration ...................................... ...... 57
3.13 Gain factor vs. tumor-to-normal beain 1 0 B concentration ........ 58
3.14 Percentage contribution of individual RBE dose components . 59
65
3.15 Subject V.A.'s right foot ..................................... ....................
3.16 Subject G .H's low er left leg ..................................................................... 66
............ 67
3.17 Subject J.Y's lower left leg ..........................................
3.18 Subject P.D .'s right leg ..................................... ......................68
3.19 Subject V.A.'s normal transverse isodoses ................................... 69
3.20 Subject V.A.'s tumor transverse isodoses ..................................... 70
71
3.21 Subject V.A.'s normal sagital isodoses .......................................
72
3.22 Subject V.A.'s tumor sagital isodoses ........................................
3.23 Subject V.A.'s normal isodoses, 25 mm inferiorly to B.C. ....... 73
3.24 Subject V.A.'s tumor isodoses, 25 mm inferiorly to B.C. ............ 74
3.25 Subject V.A.'s normal isodoses, 25 mm superiorly to B.C. ...... 75
3.26 Subject V.A.'s tumor isodoses, 25 mm superiorly to B.C. .......... 76
3.27 Subject G.H. normal isodoses, 42 mm inferiorly to B.C ............. 77
3.28 Subject G.H. tumor isodoses, 42 mm inferiorly to B.C. ................ 78
3.29 Same as Fig. 3.29 with dose to nodule at top .............................. 79
3.30 Subject G.H. normal isodoses, 75 mm inferiorly to B.C............... 80
. 81
3.31 Subject G.H. tumor isodoses, 42 mm inferiorly to B.C. ..........
3.32 Same as Fig. 3.1 with dose to nodule at right hand side ............. 82
3.33 Subject J.Y. normal transverse isodoses 34 mm supriorly to B.C. 83
3.34 Subject J.Y. tumor transverse isodoses 34 mm supriorly to B.C. 84
85
3.35 Same as Fig. 3.34 with dose to nodule at left hand side .......
3.36 Same as Fig. 3.34 with dose to nodule at top ................................. 86
3.37 Subject J.Y. normal transverse isodoses 40 mm supriorly to B.C. 87
3.38 Subject J.Y. normal transverse isodoses 40 mm supriorly to B.C. 88
3.39 Same as Fig 3.38 with dose to nodule at upper right hand ....... 89
90
3.40 Subject P.D. normal transverse isodoses through B.C .............
91
3.41 Subject P.D. tumor transverse isodoses through B.C .............
3.42 Same as 3.42 with dose to nodule (isn't visible on CT scan) ........ 92
Chapter 4
Beam Monitoring System
96
4.1 A typical beam monitor screen display ........................................
..... . 98
4.2 The second separate screen display .........................................
4.3 BN CTD OSEVI front panel ....................................................................... ... 104
105
4.4 BNCTDOSEVI portion of schematic .....................................
List of Tables
3.1 Com pund RBE Factors .......................................................................................
3.2
Summary of average 10B concentrations of subjects V.A., G.H.,
and J.Y .............................................................
................................. .......
49
61
Chapter 1
1.1
Introduction
Background
Following the discovery of the neutron by Chadwick in 1932, Gordon
Locher, a biophysicist on the staff of the Bartol Research Institute in
Swarthmore, Pennsylvania, proposed the principle of Boron Neutron
Capture Therapy (BNCT).
The basic idea behind boron neutron capture
The idea is to deliver to the cancer patient
therapy is elegant and simple.
a non-toxic boron-containing drug that is taken up only in tumor cells and
Thermal neutrons (0 to 0.1eV)
then expose the patient to a neutron beam.
produce very little radiobiological effect but they interact with the boron
to produce short range ionizing a-particles.
Thus, the tumor is selectively
irradiated while the normal tissue is spared.
This is a fundamental
advantage of binary therapies.
The two modes of the
1 0B(n,a) 7 Li
reaction are presented below:
- "He+7Li + 2.79 Me V
(6%)
-- 4He+ Li* + 2.31MeV
(94%)
'oB+l n -_ [1'B*]
7Li +
y(0.48MeV)
The main products of the above reaction are highly energetic ions,
whose range in tissue is about 10 microns.
The
1o B(n,a) 7 Li
reaction yields
high LET (Linear Energy Transfer) particles which deposit their energy
within about a cell's diameter, making them ideal for tumor cell killing.
High LET is advantageous in that it does not depend as much on the oxygen
content of the cell (and the production of oxygen radicals) as low LET
radiation, such as x-rays, does.
The biological damage caused by high LET
radiation is greater per unit dose resulting in higher Relative Biological
Effectiveness (RBE).
The reason
10 B
is used for neutron capture therapy is due to its high
cross section for thermal neutrons (3800 barns) and non-toxicity to tissue.
Also, about 20% of all naturally occurring boron is the non radioactive form
used for BNCT.
Although, thermal neutrons are used for the reaction, their
poor penetration in tissue renders them useful only for superficial tumors.
Thus, an epithermal neutron beam (1 to 10,000 eV) has been devised.
The
epithermal neutrons penetrate the tissue, and only after they slow down
and become thermalized they interact with
reaction.
10 B
to produce the desired
The success of BNCT is dependent upon selective localization of
the boronated drug in tumor and the delivery of thermal neutrons to the
desired target depth.
Thus, considerable research effort has been put into
building better epithermal neutron beams.
England Medical Center--Massachusetts
On going research at the New
Institute of Technology program
and other sites has also been dealing with new challenges in micro- and
macrodosimetry, boron compound synthesis, cellular localization, and
evaluation of its effects on normal and tumor tissues.
10
1.2
A Brief Review
of Boron Neutron Capture Therapy
Dosimetry
Neutron capture therapy dosimetry is complex in that it must take
into account contribution from different radiation components.
components
These dose
include:
* Thermal neutron dose, principally resulting from
14 N(n,p) 14 C
thermal
neutron capture reactions,
* Epithermal neutron dose, principally resulting from
1H(n,n')IH
epithermal neutron scattering reactions,
* Tissue induced gamma dose, principally resulting from lH(n, y) 2 H
thermal neutron capture reactions,
*
10 B
dose, resulting from IOB(n,a) 7 Li thermal neutron capture reactions,
* Fast neutron dose, principally resulting from
1H(n,n')IH
fast neutron
scattering reactions, but possibly including significant amounts of recoil
reactions on other tissue elements, such as carbon and oxygen,
* Reactor core gamma dose, principally resulting from gamma rays
originating in the uranium fission process in the reactor's core (core
gamma dose), and
* Neutron induced gamma dose, resulting from gamma rays produced by
the capture and inelastic scattering of neutrons by the structural
materials surrounding the beam line (structure-induced
gammas) [1,2,3]
* Gammas originating from capture of neutrons in the structural
components of the beam
The above dose components pose different radiation transport
characteristics and their dependencies on tissue inhomogeneities vary
greatly.
Since most of the tumor dose and a significant fraction of the
normal tissue dose relies on the 10B(n,a) 7 Li reaction, the dosimetry of
BNCT requires not only a detailed analysis of the radiation field produced in
tissue by the incident neutron beam, but also an accurate knowledge of the
concentration and distribution of
10 B
in tissue.
Our group has been
investigating the dosimetry of neutron capture therapy for several years
and significant progress has been made in the quantification of
[4,5,6].
10 B
in tissue
The complexity BNCT Dosimetry relative to conventional
radiotherapy is illustrated by Figure 1.1 [7], which provides the dose versus
depth for all major components in a BNCT type irradiation.
concentration of 30 ppm and a healthy tissue
are assumed for this computation.
10 B
A tumor
10 B
concentration of 7.5 ppm
These levels of boron are reasonable
examples of what is actually attainable in vivo for a boron delivering
compound such as boronated phenylalanine [8,9].
Each radiation dose component is weighted by an appropriate relative
biological effectiveness (RBE).
Each component of the dose has been
assigned an RBE value as shown in Figure 1.1.
by our group for the past few years [10].
These values have been used
RBE's are dependent on the
radiation quality, dose level, number of fractions, dose rate, and the
biological end point [11].
The complex radiation field that exists in BNCT has necessitated
the use of a sophisticated treatment planning strategy - one that allows for
the dissection of the various radiation components and the display of
resulting isodose data on existing diagnostic imaging data.
This is necessary
to provide accurate dosimetric information to correlate with resulting
pathological observations and assessment of the quality of BNCT treatment
plans.
A brief summary of a detailed manuscript describing the existing
treatment planning procedure at the interinstitutional BNCT
12
Central Axis Experimentally Measured Dose Distribution
M67 Beam, 5 MW
20
-----------
Exp Gamma RBE Dose Rate (RBE-cGy/min)
Exp Th RBE Dose Rate (RBE-cGy/min)
Exp Fast N RBE Dose Rate (RBE-cGy/min)
----
Exp B-10 RBE Dose Rate (RBE-cGy/min)
-- +--
Exp Total RBE Dose Rate (RBE-cGy/min)
15
10
C,,
0,
©
3!
5
2
4
6
8
10
12
Central Axis Depth (cm)
Figure 1.1. The measured dose rate versus depth components in a
human head phantom assuming 30ppm 10 B concentration in tumor.
The various dose components, including total dose to tumor, and the
background doses from fast neutrons, photons, and nitrogen capture of
thermal neutrons are shown separately.
13
research program between New England Medical Center and the
Massachusetts Institute of Technology is presented later in this chapter
and elswhere in this thesis [12].
1.3
Description of the Beam Monitoring System
at
MITR-II
An on-line beam monitoring system has been developed and
installed on the MITR-II medical beam [13].
The purpose of this system is
to insure that the correct dose is delivered to the patient and that no
significant changes in beam intensity, energy, or spatial distribution can
Since the dosimetry of BNCT is quite
occur without immediate detection.
complicated a number of different detectors are used.
These detectors
need to be sensitive to gamma rays, epithermal neutrons, and thermal
neutrons.
In order to determine the dose to tumor and normal tissue,
precise measurements of neutron fluence, gamma dose, and 10B
concentration are very important.
This must be done by complete
dosimetric characterization using realistic head phantoms [7,14].
The beam monitoring system also indicates any changes in beam
characteristics from those which existed when the beam was fully
dosimetrically characterized and calibrated.
The beam monitoring system,
including the radiation detectors, the readout and display system,
procedures for calibration, and the performance of the entire beam
monitor system are discussed in some detail in another paper [15].
The
focus of this thesis will be on the beam monitoring software system.
As discussed in reference [13], various fission chamber detectors are
used for monitoring the beam.
These detectors feed their signals to
14
a counter data acquisition board in a Macintosh IIci computer.
The
computer, using a versatile data acquisition and processing program called
LabVIEW 2 [16], is used to display on a 17" color monitor the detector
count rates, integral counts, dose calibration factors, target counts,
percentage of target counts, and irradiation time.
The application program
that was created using LabVIEW 2 is called the beam monitor Virtual
Instrument (VI).
Through the use of an audible alarm and a visual
warning, the beam monitor VI helps insure that the target number of
beam monitor counts is not exceeded and that the proper dose is delivered.
Numerical and analog graphical displays of the count rates and total counts
are presented on the CRT on the screen, and the software has been
programmed to detect discrepancies in the detector counts that can be
caused by beam non-uniformity, asymmetry or intensity.
The beam
monitor outputs are directly related to patient dose through intercalibration with the phantom dosimetry measurements as discussed above.
These doses are computed on-line by the BNCTDOSE VI that has been
added to the beam monitor VI.
More details on the modifications are
presented in Chapter 4.
1.4
An Outline of the Steps Involved in a BNCT
Treatment
Plan
A treatment planning technique has been developed in our group to
provide the ability to incorporate the various dose components of the
complex radiation field that is produced in a BNCT irradiation [17].
Using a
dedicated program for BNCT treatment planning, NCTPLAN, our group has
developed the ability to superimpose dose isocontours on diagnostic
15
images of the human anatomy.
NCTPLAN is described in more detail in
Chapter 3.
NCTPLAN Monte Carlo Treatment
Planning for BNCT
CT or MRI scans
Monte Carlo
Simulation
(MCNP)
Figure
between
therapy
Medical
Experimental
Normalization
1.2. Schematic representation of the flow of information
the functional modules of NCTPLAN, the neutron capture
treatment planning program devised by the New England
Center--Massachusetts Institute of Technology joint program.
NCTPLAN constructs a mathematical model of any body part using
the anatomic geometry and tissue type data obtained from CT scans by
assigning a material type of either bone, air or soft tissue to a given three
dimensional voxel (lcm 3 ). Tumor region and
specified manually by the operator.
10 B
concentrations are
Then, NCTPLAN transfers the details
of the model, a so called materials file, to a Monte Carlo based radiation
16
transport code called MCNP.
MCNP simulates the irradiation of the model
by an epithermal neutron beam, whose properties are identical to the
MITR-II epithermal neutron beam - currently, the M67 beam.
All the
dose components of the voxels are computed independently and the
resulting dose file is transferred back to NCTPLAN for generation of dose
iscontours.
These dose isocontours can be generated for an arbitrary plane
and superimposed on the reformatted CT scan images for ease of
evaluation.
Figure 1.3 shows an example of tumor brain RBE-isodose contours
computed by MCNP and displayed by NCTPLAN for a parallel-opposed
irradiation of the head.
Our thanks to patient S.M. for volunteering for the
CT scanning procedure that was necessary to produce the CT scan data
used for Figure 1.3 and other figures in this work.
17
·_^ · I__
Subject: Test
Date: 6195
Beam: M67115 cr
Orientation: P-OTumor PPM: 40.(
Normal PPM: 10.
Normalization: 2:
# Fractions: 1
Isodoses: Tumor
RBE Set: BNL
-:
MIT
BNCT
Figure 1.3. Tumor isodose contours computed by NCTPLAN in a
transverse plane through head of subject using lateral parallel-opposed
irradiation with M67 epithermal neutron beam. Assumed 10 B
concentrations are 10 ppm in normal brain tissue and 40 ppm in tumor.
1.5
Thesis
Objectives
and Outline
The aim of this work is the development of an improved treatment
planning software for the boron neutron capture therapy trials at the
New England Medical Center--Massachusetts Institute of Technology joint
program and to facilitate the future operation of the treatment planning
procedure.
A detailed documentation of every step in the treatment
planning procedure, starting with CT scans and leading to RBE-dose
isocontours, is presented in the first part of the thesis.
18
Several treatment
plans of subjects irradiated as part of the phase-I boron neutron capture
therapy dose-escalation melanoma protocol have been prepared by the
author and are presented as examples of the use of NCTPLAN.
The second part of the thesis focuses on the on-line beam monitoring
system.
The aim of the modified beam monitor software is to eliminate
the need for the use of BNCTDose, a MathCAD based dose calculating
program, and KleidaGraph for fitting a double exponential (of a
predetermined shape) to the blood uptake curve in order to determine the
instantaneous blood concentration during an irradiation.
The improved
beam monitoring software automates the task of calculating the
instantaneous blood concentration which is inputted into the dosimetry
equations to calculate new irradiation times, and target monitor unit
counts.
Simulated runs of the modified software, beam monitor virtual
instrument, are also presented.
Chapter 2 describes the operational procedures involved in a
treatment plan.
Chapter 3 discusses NCTPLAN in detail.
Chapter 4 gives
an overview of the beam monitoring system and describes the
modifications done to the software.
Chapter 5 presents some results from
the modifications done and discusses future improvement to the New
England Medical Center--Massachusetts
planning
procedure.
19
Institute of Technology treatment
Operational Procedures
Chapter 2
2.1 Extracting Images
from the
CT Scanners
The first step in every treatment plan of a BNCT experimental
subject is to obtain either a Computer Tomography (CT) scan or a Magnetic
Resonance Image (MRI) of the area to be treated.
At the New England
Medical Center--Massachusetts Institute of Technology joint program a
thin-slice CT image data is used to create the input file to MCNP.
Up to 250
contiguous 2mm CT scans of the subject's relevant body part are acquired
using one of the three General Electric Advantage-HS CT scanner with
helical spanning capability.
The technique factors that are employed are
120 kVp, 100mA, 1 second helical scan, gantry angle set at zero, and a
hardware zoom factor of 1 for larger body parts and 2 for heads [10].
No
contrast is used because that would interfere with the quantitative method
that is employed to determine tissue type.
Following a CT scan of the subject, the images are transferred to a
Digital Equipment Corporation (DEC) Station 5000 via an ethernet
communication link.
1.
The procedure is as follows:
Log into the DEC station named ANTARES (Internet Protocol address:
155.36.40.155):
username: mcnp
password:
2.
*****
Telnet over to one of the GE scanners (which ever one the optical
disk is inserted in) by typing:
20
(for ctroom3 scanner; 155.36.40.134
telnet 155.36.40.136
and 155.36.40.135 refer to the other two CT scanners, ctrooml
and ctroom3 respectively)
3.
The machine will prompt you for a username and a password:
username: genesis
password:
4.
*****
To extract the images from the GE scanner to the scanner's public
directory enter the command,
srt_copy EE SS II
where EE is the exam number (e.g. 6047)
SS is the series number (e.g. 2)
and II is the image range that you wish to copy (e.g. 1-123).
If there are any problems with the image transfer you can view the optical
disk (under select drive - optical disk) in the CT scanner room.
if the images are being extracted directly from the optical disk and not
from the hard drive in the GE scanner than follow the image range with
"-o", e.g. srt_copy 6047 2 1 1-123 -o).
The CRT display will then show the images being extracted, giving a
message such as
Extracting image E6047S211.CT
for each image requested.
per image.
This process takes approximately 5 seconds
For reference, the image data are stored on the CT scanner's
hard drive in the public directory
/usr/g/insite/tmp.
To check if there is
enough room on ANTARES one can type df (>30,000,000 bits are necessary
for these images).
The above procedure is also possible from the Radiation
Oncology's SRT system node STEREO.
21
After the images are brought over to
A fast
the DEC station they need to be decompressed and unpacked.
program has been written to do this.
The output of the program is
images that are in the format expected by the SRT (Stereotactic Radio
Therapy) system.
A script program has been written to transfer the
images from the CT scanner to the DEC station.
To invoke it one needs to
log onto ANTARES and type the following:
cd geprogs
ge_copy ctroom3 (ctroom3 is an alias to the CT scanner in room
three)
This runs a script that invokes file transfer protocol, FTP, to transfer the
public files to the DEC station.
The resulting files are put in directory
ANTARES/usr/users/images/boron/new_images
and are always
names
"gect.CT#", where # is the sequence of the image in the series.
Now, if one would like to list the file one can type,
tapext-nemc G -1
To decompress the files and convert them to SRT format,
tapext-nemc G -I
ANTA RES/usr/users/images/boron/new_images/<name>. -s
0-122
Note that the list of images should specify numbers that are one less than
the image sequence numbers.
In the above example there are 123 images
that are numbered 1-123 in the series.
The result of the above command
will be in two files, e.g.:
<name>_01.10.96.0.header - contains specs for the CT scan
<name>_01.10.96.0.img - contains all images in a single file.
The images are stored in a row wise, first image to last, 512x512 pixels,16
bit format.
Data values in the .img file are 0-4095, representing the CT
numbers offset by 1024 (i.e., -1024 to 3071).
22
2.2
Importing Images
to the VAX
Computer
The SRT image files are now located on the DEC station and need to
be transferred to the Digital Equipment Corporation VAX 3900
microcomputer where NCTPLAN is currently located.
On the VAX, the
images are first converted to the format that is used by the Image
Analysis Lab (IAL).
VAX.
To start the image transfer one needs to log onto the
This can be done from ANTARES by typing:
telnet
rigel.medphysics.nemc.org (or telnet 155.36.40.150)
username:
bnct
password:
*****
Once logged in, the user is located in the SYS$SYSDEVICE:[BORON]
directory (also known as device $3$DIA40).
Now, before starting the
image transfer, it is wise to check if there is enough room on the VAX
storage device.
This can be done with the command: show dev d, which
gives a listing of the different devices (disks) and the space available on
each.
After making sure that there is enough space on the current disk (or
changing to a different disk using the set default <device-name> command),
new directories need to be created for the new subject's images.
This can
be done the following way:
$ create/dir [.subject_name]
$ create/dir [.subject_name0]
The first is a directory for the execution and script files that are specific
for the subject.
The second directory is for the patient images.
directories will be created automatically in $3$DIA40:[BORON].
verified by typing more /etc/hosts.
23
These
This can be
Now, the following will transfer the files to VAX (node Rigel):
$ cd [.subject_name]
$ ftp
antares.medphysics.nemc.org
rigel.medphysics.nemc.org Multinet ...
connection opened
antares ftp server ... ready
login: mcnp
antares.medphysics.nemc.org>
password: *****
antares.medphysics.nemc.org>
cd/us r/users/imag es/bo ro n/new_ ima g es/
antares.medphysics.nemc.org>
get <name>_01.10.96.0. header
to local file (on the VAX): dub0:[img.boron<name>_01.10.96.header
antares.medphysics.nemc.org>
antares.medphysics.nemc.org>
binary
get <name>_01. 10.96.0. img
to local file (on the VAX): dub0:[img.boron<name>_01.I0.l96.img
Now, it is possible to convert the files to the Image Analysis Lab's .bin
format.
This is first done by modifying the command procedure in the file
CONVERT_SUBJECT_NAME.COM to reflect the names of the new input file
and the starting binary output file, *.BIN.
Also, since this is an execution
file you should be in the subject_name directory, but for the output
directory that you use in convert_subject_name.com
the subject_name0 directory.
you need to use
To do the above, first copy
CONVERT_SUBJECT_NAME.COM to the new subdirectory that you just
created by typing
$ copy
[000000.previoussubject name]convert_previos_subject_name.com
[000000.subject_name]convert_subject_name.com
24
$ tpu
convert_subject_name.com
$ rename *.srt *.img
$ submit convert_subject_name (or @convert_subject_nane)
This is a batch job that takes about five minutes to complete (for about
125 images).
You will be notified when the job is completed and a log file
in the home directory called CONVERT_SUBJECT_NAME.LOG will show the
output.
The result will be files in the following form:
<subj ect_name>001 .bin
<subject_name> 123.bin
Once in a while it is important to erase old copies of files in the directories.
This can be done with the purge
command.
Now, the images are ready to
be used by the Image Analysis Lab's Image Executive program, IMEXEC, to
extract the boundaries between the different tissue type and prepare the
MCNP input materials file.
2.3
Extracting
Tissue/Bone
Boundaries
The input required by MCNP is a list of cells (called voxels) whose
content of each cell is specified in terms of the percentages occupied by air,
tissue, tumor, or bone.
Each tissue type can take on a cell volume fraction
value of either 0, 20, 40, 60, 80 or 100%, which yields all together 56
different materials.
Since there are dense objects present in the field
besides the object of study, and because normal and tumor tissue are not
easily distinguished, boundaries must be determined between the object
(subject or phantom) and air, and between normal tissue and tumor tissue.
The program IMEXEC is used to draw these boundaries, as well as to
25
determine the cell composition list.
Object/air boundaries are determined
automatically once a starting point is specified and tumor/tissue
boundaries are drawn manually by hand using a mouse.
Tissue/bone
boundaries are not explicitly obtained, but are computed implicitly from a
threshold
value.
These boundaries are used by NCTPLAN to (1) generate an "icon" (i.e.,
a line drawing which stacks the object contours from all CT slices at the
viewing angle), and (2) identify the points where the beam enters and
exits the object.
beam plot.
The latter are shown both in icon and in one dimensional
Tumor boundaries are used only to tell where the tumor is
when analyzing the slices for their cell component with IMEXEC.
Two
IMEXEC script files (also called playback files) are used to find the object
boundaries.
The first script file invokes the second, so the operator need
only be aware of their combined operation.
The result is a single
"boundary file" containing all the boundaries, e.g., SUBJECT_NAME.BND, or
MEDHP.BND for the medium head phantom.
The scripts are just list of
instructions that are fed in sequence to IMEXEC which direct it through
various menus, selecting the desired commands and options.
Thus, the
operation of the scripts can be duplicated from the terminal by keying in
one command at a time.
The script files BOUNDI.PLA and BOUND2.PLA are specific to a
subject and need to be modified to accept other image sequences.
Using
the TPU editor that's available on the VAX computer, one will need to
change the threshold, the starting file name (first image showing the
object), and the boundary file name for each subject.
After modifying the
above files the scripts can be invoked from IMEXEC in the following way:
26
$ IMEXEC /X
initialization
menu)
I
(enters
7
Y
8
BOUNDI.PLA
E
(selects option to enable/disable playback mode)
(turns on the playback options)
(selects option to change the playback file name)
(specifies the playback file)
(exits the menu and starts the playback file)
After a few seconds an image will appear on the monitor with the
Boundary Trace menu on the terminal window.
At the bottom of the
screen you will see a diagram indicating the four functions that are
accessible through the mouse buttons.
The program will be waiting for the
user to move the mouse (a cursor will track it on the screen) and to push a
button indicating the selection of the user.
Move the cursor to the left of
the object and press the "Auto start right" button and then the "Return to
menu" button.
If the computer doesn't get the boundary the first time, try
again with a new starting point.
If the image has more than one boundary
that needs to be drawn type G_optimize start and then shift+B. When the
boundary tracing menu reappears, type * at the prompt for "Selection:".
This will repeat the playback file for the next image.
for all images this way.
Get the boundaries
Once the procedure has been mastered the process
can be made faster by typing IMEXEC /b.
This will surpress menus.
Once the boundaries have all been completed they can be read back
for approval with a script file similar to that contained in the command
procedure SHOW_MEDHP.COM.
To run such a procedure, first modify the
file to reflect the current subject and associated files.
Then. save as
SHOW_SUBJECT_NAME.COM and execute the following way:
$ @SHOVW_SUBJECT_NAME_BOUND x
27
or enter the commands one at a time from the terminal keyboard.
If
boundaries need to be deleted use a text editor (such as TPU or EDT) to
eliminate them from the boundary file.
A copy of all the script files
mentioned above is included at the end of this chapter.
If an image is found where the boundary needs to be fixed (i.e.
image #8), than go through the following command sequence:
$ IMEXEC /x
I
9
Y
10
subject_name8.bnd
E
R
subject_nameO08.bin
E
S
B
BF
subject_name8.bnd
IT or MT (depending on whether you want to do a Manual Trace or
auto trace)
WB
E
E
To fix the file subject_name.bnd replace the portion that corresponds to
image #8 with the new boundary file: subject_name8.bnd.
done using the TPU editor in the following way:
$ TPU subject_name.bnd
PF4 (command)
find
subject_name008
PF7 (mark)
PF8 (delete)
PF4
include
28
This can be
subject_name8.bnd
PF4
save file
CTRL- Y
Now, the boundary file is ready to be used as the basis for making the
materials file and for the icon in NCTPLAN.
2.4
Preparations for MCNP Dose
Computations
To prepare the materials file that is used in the MCNP dose
calculations follow the command sequence in analyze_subject_name.com.
Since this file needs the beam direction as input and threshold between
bone and soft tissue, it is best to modify it with the help of the medical
physicist.
To obtain the threshold type:
$ IMEXEC /x
R
V
T
Once the beam direction has been specified and put in to
analyze_subject_name.com,
the use can run the script file
automatically
by typing:
$ @analyze_subject_name.corn x
This takes about 25 minutes to run.
materials
The output of this procedure is the
file, subject_name.mea.
A fast (TI) link between the Massachusetts Institute of Technology
and the New England Medical Center facilitates the file transfer procedure.
to transfer the materials file follow the command sequence described here
forth:
29
$ boron
$ ftp 18.149.0.38
(this changes to the MCNP input data directory)
(this is the host address of the MIT site)
After the remote system prompts you for a login, type anonymous. Use
you full e-mail address as the password.
an anonymous File Transfer Protocol (FTP).
This is the accepted standard for
You are now connected to MIT.
In order to move the materials file to MIT type the following,
>
>
>
>
>
cd pub
cd NEMC
put subject_name.mea
ls
quit
The results of the MCNP runs are put in the subject_name directory with
the .elr extensions, representing the dose input file to NCTPLAN.
Script Files
2.5
* subject_namel.pla
C
R
9
subj ect_name0000.bin
I
9
Y
10
subject_name.bnd
S
B
2
M
IP
1
5
2
L
30
7
Y
8
su bj ec t_n ame 2. pl a
*
subject_name2.pla
R
IR
S
B
IT
WB
11
0
I
7
R
I
7
Y
Sshowsubj ect_name_bound.co m
$ bnd to bnd
subject_name.bnd
* analyze_subject_name.com
$
$
$
$
$
subject_name
set output_rate=0:0:1
set noon
set verify
IMEXEC /x
! Initialize
Measurements'?
I File name
subject_name.mea
31
E
! Exit initialize
S
! Scene segmentation
B
! Boundary algorithms
BF
! Boundary file name
subjectname.bnd
OB
E
! Exit boundary algorithms
E
! Exit scene segmentation
P
! Special Procedures
N
! NCTPLAN menu
I
! Base file name
s ubj ect_name00000. bin
2
! X-Y scale (mm/pixel)
0.47
3
! First slice (slice #65 is the center in this case)
4
4
! Number of slices to analyze
123
7
! Air/Tissue threshold
20
I Bone/Tissue threshold
80
Central voxel X
10
Central voxel Y
Display central voxel
Specify beam direction
Display beam direction
-25.29
55.67
0.0
-25.59
-26.10
0.0
! Display beam direction
it
It
n
32
! X,Y,Z of entry
! X,Y,Z of exit
C
6.0
6.0
S
O
E
E
E
Specify boron con centration
Normal tissue
Tumor
Auto analyze stack
Output data file
Exit
33
Chapter 3
3.1
NCTPLAN
Background
NCTPLAN is a Monte Carlo based treatment planning code written for
boron neutron capture therapy at the New Englasnd Medical Center-Massachusetts Institute of Technology joint program.
This code has been
used to plan the treatments of four experimental subjects up to date ["8].
The importance of having a good treatment planning code is not only to
optimize the dose delivery to tumor, but also to provide a dosimetricpathologic correlation in those subjects that do not survive the
experimental therapy.
This will allow for a better understanding of the
dose response properties of this new radiation modality to be better
understood.
Since the radiation field of a BNCT treatment consists of four
distinct dose components that possess different radiation transport
characteristics it is important to use a Monte Carlo simulation which yields
accurate results.
Accuracy is of paramount importance resulting in long
computation times in the initial study.
The purpose of this chapter is to
describe the concept that went into the design of NCTPLAN, present
illustrative applications and sample treatment plans of experimental
subjects, and finally, to document a user's manual for the program.
34
3.2
MCNP Dose Computations
IMEXEC has a build in feature that works in conjunction with
NCTPLAN to produce a volume-weighted materials file.
This material file
assigns each of the 11,025 cells (21x21x25 cm) a material number from 1
to 56 which corresponds to the different mixtures of tumor, normal tissue,
bone, and air.
Figure 3.1a shows a transverse CT image of a pateint's head
through the plane of the orbits.
Figure 3.1b shows the corresponding
material image as automatically computed by NCTPLAN.
It should be
noted that the gray scale used in in Fig 3.1b represents material's
numbers, and thus does not correlate with the x ray linear attenuation
coefficient gray scale used in Figure3.1a.
0%
4
(a)
(b)
Figure 3.1 a) 2 mm thick transverse CT scan image through the plane of
the orbits. Gray-scale corresponds to X-ray linear attenuation coefficients.
b) Corresponding transverse "material" image. 56-level gray scale
corresponds to material numbers (each material consisting of a defined
proportion of air, normal soft tissue, tumor tissue, and bone).
35
When the treatment plans are computed for the brain, tumor and
normal tissue have the same elemental composition of average "brain", but
differ by their assigned concentrations of
1 0 B.
When treatment plans are
computed for other parts of the body, such as limbs, tumor and soft tissues
are assumed to have an elemental composition of "muscle", which is also
modified for the different assigned concentrations of
10 B.
There is no
significant difference in the radiation transport properties between brain
and muscle tissue, except that brain has a considerably lower nitrogen
content relative to muscle.
This affects the thermal neutron dose, which is
lower due to less 14 N(n,p) 1 4 C reactions.
The explicit inclusion of
10 B
in the
Monte Carlo model has previously been shown to be potentially important
with respect to correcting for depression of thermal neutron flux, and,
therefore,
10 B
dose and thermal neutron dose [15].
R.G. Zamenhof et. al.
showed that along a 35 eV monoenergetic epithermal electron beam there
is approximately a 0.4% depression in thermal neutron flux per each
incremental +1 ppm of
10 B.
If the normal brain contained 20 ppm of
10 B
during irradiation, the true and thermal neutron doses would be lowered
by up to 8% [10].
Thus, it is important to include the effect of
10B
in the
soft tissue material formulation.
A materials file provides the MCNP program with 11,025 1 cm 3 cells
whose X-Y-Z oordinates and material content are specified, and the beam
entry and exit points.
A short Fortran program was written to convert
these data points into the standard format required by Monte Carlo code.
The Monte carlo simulation code used for the BNCT treatment
planning is MCNP (Monte Carlo N-Particle transport), version 4a, installed
on a Sun Sparc Workstation 670MP running 4 processors in parallel.
code, which was originally developed for weapons research at the Los
36
This
Alamos National Laboratory (LANL) [19], is probably the most sophisticated
code of its kind from the perspective of the physics employed and a large
development and support staff at the LANL.
neutron/photon code.
MCNP is a coupled
That is, it has the capability to handle photon
production by neutron interaction without requiring the generation of a
photon source and independent photon transport simulation.
This code
uses pointwise continuous energy cross section data from various sources
at the moment of any specific neutron or photon interaction.
The actual
energy of the particle determines the interpolated cross section.
The
energy density of the cross section data is such that interpolation between
points results in less than a 1% discrepancy in reproducing the
experimental cross section data.
A beam source was computed from Monte Carlo runs simulating the
MITR-II's reactor core and all relevant surrounding structures
[20].
This
source was than used to calculate the transport of neutrons and photons
through the filter elements of the epithermal beam line and 15 cm
diameter beam delimiter resulting in a final 15 cm diameter epithermal
neutron beam source located at 1 cm above the uppermost location of the
subject's body part [21].
This simulates the present "M67" epithermal
neutron beam that has been employed for clinical studies.
To compute
absorbed doses in tissue, a feature of MCNP was used which allows
arbitrary nuclear reaction rates to be computed as part of the simulation
(e.g. heat production by neutrons and photons).
This feature allows the
computation of the integral products of the neutron or photon flux spectra
and energy dependent fluenc-to-KERMA (Kinetc Energy Released in
MAtter) conversion factor corresponding to each material either explicitly
or implicitly specified in the model [22].
37
A more detailed description of the
Monte carlo simulation that is used with NCTPLAN is available in reference
[10].
3.3
Program Architecture
The MCNP output files resulting from the required Monte Carlo
simulations are stripped of most of the output data since it is not required
by the present application and are combined into one file that constitutes
the NCTPLAN input dose file (usually subject_name.elr).
NCTPLAN can generate one-dimensional dose profiles along any
arbitrary axis, two-dimensional isodose contours in any arbitrary plane,
various figures-of-merit specifically designed for BNCT treatment planning,
and other visual displays of combined dose and CT image data.
One-
dimensional data presentation is accompanied on the computer screen by a
realistic three-dimensional "icon" of the body part being examined,
showing the orientation of the cartesian coordinate system, the direction of
the incident neutron beam(s), and the axis along which graphical data are
displayed.
This icon is an actual three-dimensional surface rendered
image of the relevant body part constructed of contours automatically
derived from the original CT images.
To facilitate treatment planning, two-
dimensional isodose contour displays are precisely superimposed on
corresponding reformated CT images.
The images preserve the original
high-resolution of the CT scans thus maintaining visibility of small
anatomical
structures.
Automatic isocontouring is extremely difficult when the raw data
reside in a coarse spatial matrix such as the 1 cm x 1 cm x 1 cm cell
structure used.
Consequently, the first of two stages of data processing
38
prior to isocontouring involves the interpolation of the raw dose-rate data
onto a much finer 1 mm x 1 mm x 1 mm matrix.
interpolation in three dimensions.
This is achieved by linear
Each coarse dose-rate value is ascribed
to the geometrical center of its original 1 cm 3 cell.
by straight lines called "primary interpolators".
Such centers are joined
A new 1 mm 3 voxel is
selected and a "web" of primary interpolators is constructed using nine
contiguous cells centered on the new 1 mm 3 voxel.
A line is constructed
which is the shortest line passing through the new 1 mm 3 voxel and two of
the nearest primary interpolators; this line is called a "secondary
interpolator".
The value of this voxel is then calculated by linear
interpolation along the primary interpolators, to obtain the values of the
intersection points of the secondary interpolator with the two primary
interpolators, and then along the secondary interpolator to obtain the final
value of the 1 mm 3 voxel.
The resulting interpolated three-dimensional
dose matrices are
processed using a three-dimensional Fourier transform and a ramp type
frequency-space filter function having a cut-off at 0.5 cycles/mm.
This
process "irons out" some of the high spatial dose gradients caused by a
combination of the statistical fluctuations in the Monte Carlo calculated
doses and the interpolation process itself.
It was found from experience
that the isocontouring algorithms that are applied to the two-dimensional
dose arrays did not perform well in the absence of this maneuver.
Voxels that are outside the "skin" of voxels defining the outer
surface of the model contain dose values that are only virtual, since with
no tissue present there is no dose per se despite the existence of computed
neutron and photon flux values.
If these virtual dose values were allowed
to remain the isocontouring process would be greatly complicated,
39
producing isodose contours running from inside the model into the space
outside, with no possibility for contour closure.
To avoid this problem the
second stage of data processing allows these virtual dose values to remain
during the interpolation of the coarse dose data into the 1 mm 3 voxels, but
prior to isocontouring all virtual dose values are set to zero.
This approach
is not used in the case of cells representing internal voids, since what may
appear in a CT image as an internal void may in fact contain low-density
tissue for which it may be important to obtain an estimate of dose.
The
isocontouring algorithm employed is in the category of heuristic search
algorithms, which were found to be more immune to "getting lost" in
regions of low dose gradient due to the residual random noise in the dose
data.
Flux-to-KERMA conversion factor files used to convert neutron and
photon fluxes to dose-rates are based on KERMA values for soft tissue
(average brain or muscle, with specified concentrations of B-10) even if
the dose location happens to correspond to bone or a soft tissue/bone
mixture.
It is the dose to the osteocytes and other cells within the
mineralized bone matrix that is probably of greater clinical importance
than the dose to the mineralized bone matrix per se.
Automatic isocontouring is extremely difficult when the raw data
reside in a coarse spatial matrix such as the 1 cm x 1 cm x 1 cm cell
structure used.
Consequently, the first of two stages of data preprocessing
prior to isocontouring involves the interpolation of the raw dose-rate data
onto a much finer 1 mm x 1 mm x 1 mm matrix.
interpolation in three dimensions.
This is achieved by linear
Each coarse dose-rate value is ascribed
to the geometrical center of its original 1 cm 3 cell.
by straight lines called "primary interpolators".
Such centers are joined
A new 1 mm 3 voxel is
selected and a "web" of primary interpolators is constructed using nine
40
contiguous cells centered on the new 1 mm 3 voxel.
A line is constructed
which is the shortest line passing through the new 1 mm 3 voxel and two of
the nearest primary interpolators; this line is called a "secondary
interpolator".
The value of this voxel is then calculated by linear
interpolation along the primary interpolators, to obtain the values of the
intersection points of the secondary interpolator with the two primary
interpolators, and then along the secondary interpolator to obtain the final
value of the 1 mm 3 voxel.
The resulting interpolated three-dimensional dose matrices are
processed using a three-dimensional Fourier transform and a ramp type
frequency-space filter function having a cut-off at 0.5 cycles/mm.
This
process "irons out" some of the high spatial dose gradients caused by a
combination of the statistical fluctuations in the Monte Carlo calculated
doses and the interpolation process itself.
It was found from experience
that the isocontouring algorithms that are applied to the two-dimensional
dose arrays did not perform well in the absence of this maneuver.
Voxels that are outside the "skin" of voxels defining the outer
surface of the model contain dose values that are only virtual, since with
no tissue present there is no dose per se
computed neutron and photon flux values.
despite the existence of
If these virtual dose values
were allowed to remain the isocontouring process would be greatly
complicated, producing isodose contours running from inside the model
into the space outside, with no possibility for contour closure.
To avoid
this problem the second stage of data processing allows these virtual dose
values to remain during the interpolation of the coarse dose data into the
1 mm 3 voxels, but prior to isocontouring all virtual dose values are set to
zero.
This approach is not used in the case of cells representing internal
41
voids, since what may appear in a CT image as an internal void may in fact
contain low-density tissue for which it may be important to obtain an
estimate of dose.
The isocontouring algorithm employed is in the category
of heuristic search algorithms, which were found to be more immune to
"getting lost" in regions of low dose gradient due to the residual random
noise in the dose data.
Flux-to-KERMA conversion factor files used to
convert neutron and photon fluxes to dose-rates are based on KERMA
values for soft tissue (average brain or muscle, with specified
concentrations of B-10) even if the dose location happens to correspond to
bone or a soft tissue/bone mixture.
It is the dose to the osteocytes and
other cells within the mineralized bone matrix that is probably of greater
clinical importance than the dose to the mineralized bone matrix per se.
3.4
NCTPLAN Results and Validation
The results of NCTPLAN must be validated using experimental mixed
field dosimetry methods.
The method of in-phantom paired ionization [23]
techniques was applied by Rogus [7] to the dosimetry of the M67
epithermal beam at the MITR-II Research Reactor.
An acrylic shell water-
filled calibration phantom has been used for experimental validation of the
computationally derived dose distribution.
routine beam calibrations.
This phantom is still used for
A diagram of the acryllic shell water-filled
calibration is presented in Figure 3.2.
The design and specification of this
phantom are described in Harling [24].
The experimental phantom was
scanned in a CT scanner at the New England Medical Center and the images
were processed as described above.
42
A monte Carlo model was
MITR-II M67 Epithermal Neutron Beam
I
TE /CG
Io
IYI
H , 1`~H20
L-i
11I
LI'i
Figure 3.2 Diagram of water and Lucite calibration phantom used for
experimental validation of computationally derived dose distributions and
for routine beam calibration. Arrows indicate orientation of the neutron
beam during irradiation.
automatically constructed, the MCNP code was used to calculate the three
dimensional dose matrix for the model, and NCTPLAN was used to process
and display the resulting doses.
The copmputed dose rates along the
central axis of the experimental beam were used then compared to the
experimentally measured values.
Minor linear adjustments were made to
43
the computed individual dose components to provide a better absolute
agreement with the experimental rsults, but no modifications were made
to the shapes of the computed dose vs. depth curves.
Figures 3.3-3.7 show comparisons between the calculated and
measured central axis physical dose rate vs. depth data in the calibration
phantom specified for muscle.
Note that the total dose components in
Figure 3.7 are not weighted by RBE factors, as they would for an actual
treatment plan.
A good fit to the experimentally derived dose rate data is
achieved with some adjustments (multiplicative factors are described
within the captions).
A possible reason for that is that the actual dose
rates at the subject irradiation position are influenced by factors such as
the actual number of fuel elements used, their precise position, degree of
fuel burnup, control blade height, etc., which are represented by their
averages in the MCNP model of the reactor core.
To illustrate the use of the NCTPLAN treatment planning program, a
treatment plan was obtained for a glioblastoma patient.
The
biodistribution of the BPA boron compound assumed for this patient is
based upon actual boron analyses of tumor and blood biopsy specimens
that were obtained from a number of patients following intravenous
[25]. The
administration of BPA-Fructose
10B
concentrations at time of
neutron irradiation are assumed to be 40 ppm in tumor and 10 ppm in
Compound-RBE (C-RBE) factors are applied
blood and normal brain tissue.
to each of the dose components.
C-RBE factors are experimentally derived
and are the products of the "intrinsic" RBE and the "compound factor" [10].
Compound factors modify the intrinsic RBEs to account for differences in
microdosimetry, based on
10 B
distribution and cellular microanatomy [26].
The values are presented in Table 31.
44
0.4
. 0.3
0.2
0
a,
0
2
4
6
8
10
12
Central Axis Depth (cm)
Figure 3.3 Thermal neutron dose rate with a 0.87x absolute adjustment
factor applied to the NCTPLAN data.
45
1.5
S1
0
z
ro.5
0.5
0
Central Axis Depth (cm)
Figure 3.4 Epithermal and fast neutron dose rate with a 0.75x absolute
adjustment factor applied to the NCTPLAN data.
46
C
4
S3
02
1
0
Central Axis Depth (cm)
Figure 3.5 1 0 B dose rate assuming 10 ppm 1 0 B concentration with a 0.87x
absolute adjustment factor applied to the NCTPLAN data.
47
03
a,
2
C,
0
1
0
Central Axis Depth (cm)
Figure 3.6 Total gamma dose rate: phantom induced + beam-line
structure-induced gammas + 0.8x beam-line structure induced gammas.
The last component of the gammas is a surrogate representing the reactor
core gamma component which is presently not amenable to computational
derivation.
48
10
2
Central Axis Depth (cm)
Figure 3.7 Total dose rate in normal brain (assuming 10 ppm of 10B) and
in tumor (assuming 40 ppm of 10B).
Table 3.1
Compound RBE factors used for summing dose components.
The two different C-RBE values for gamma rays are based upon the
assumption that cranial BNCT treatments will be delivered in either a
49
single irradiation or in four fractions (see discussion later in this section)
and are derived from [27].
The C-RBE value of 3.2 for neutrons is based on
experimental data in normal rat brain, and the C-RBE values for
10B
dose in
tumor and normal brain are based on experimental data in GS9L
inracranial tumors in rats [10] and spinal cord injuries in rats [28]. The
large differences in the two latter values reflect the apparently large
differences in
10 B
microdosimetry in the two animal models.
These C-RBEs
are the same as the ones used at the Brookhaven National Laboratory BNCT
studies [8].
Figure 3.8 shows normal brain iso-RBE-dose (hereafter referred to
as isodose) contours computed by MCNP and displayed by NCTPLAN for a
parallel-opposed (POP) irradiation of the head.
The plane displayed
corresponds to the beam's central axis and to the widest transverse section
of the brain where, in this particular subject, no gross tumor is evident.
The treatment planning protocol employed at NEMC-MIT designates 95% of
the absolute maximum normal tissue dose as equivalent to "100%" on the
isodose display.
This is based on the assumption that a dose hot-spot at a
point is probably less clinically relevant that a 5% lower dose within a
tissue volume of approximately 3-6 cm 3 , which would approximately be
the volume of tissue receiving 90-100% of the absolute maximum dose.
Figure 3.9 shows isodose contours calculated for tumor within the
same anatomical plane as displayed in Figure 3.8.
The tumor isodoses are
normalized to the 100% normal tissue dose, i.e., to the same normalization
value as in Figure 3.8.
Thus, "150%" means that tumor lying under that
isodose contour receives 50% more RBE dose than the 100% normal tissue
value.
defined
It can be seen that with the M67 epithermal neutron beam and the
10B
distribution parameters, tumor at the brain midline would
50
receive approximately 1.6-1.7 times more RBE dose than the defined 100%
reference value in normal tissue.
However,
tumor located more
superficially but still along the beam's central axis, could receive up to 2.3
times more RBE dose.
Figure 3.10 shows normal tissue isodose contours constructed for a
coronal plane through the orbits.
It can be seen that in this specific
example the orbits receive 70-80% of the maximum RBE-dose to normal
brain.
Estimates of RBE-dose to other normal structures within the brain,
such as the brainstem, adenohypophysis, etc., can be obtained in a similar
fashion by reconstructing the appropriate isodose and anatomical planes.
The following study is taken directly from [10].
A parametric
analysis was conducted to examine the tradeoff in "gain factor" by
increasing the concentration of
10B
10 B
in tumor and by increasing the ratio of
concentrations in tumor to that in normal brain.
The "gain factor" is a
figure of merit defined here as the ratio of tumor RBE-dose-to-normal
tissue reference RBE dose; for wherever the tumor's location happens to be.
Figure 3.11 shows the same anatomical plane as shown in Figure 3.10
except that a small tumor is assumed to lie at the brain midline arbitrarily
containing 80 ppm of
1 0 B.
The gain factor is directly obtained by
estimating from the isodose contours the RBE-dose which includes the
assumed tumor.
Figure 3.12 shows a plot of the gain factor vs 10B
concentration for this tumor for various tumor-to-normal brain
10 B
ratios.
It can be seen that little additional gain ratio is accrued beyond a tumor
10B
concentration of approximately 120 ppm at tumor-to-normal brain
ratios of 3-4:1, which are typical for the BPA compound.
Figure 3.13
the tumor-to-normal brain
shows a plot of the gain factor vs
various concentrations of in tumor.
51
10 B
10 B
It can be seen that at tumor
ratio for
10 B
concentrations of 30-50 ppm (typical for the IV administered BPA
compound), little additional gain factor is accrued beyond tumor-to-normal
brain
10B
ratios of approximately 7:1.
It is evident, however, that with
10B
improved boron compounds possessing higher tumor-to-normal brain
ratios and/or attaining higher tumor
10 B
concentrations,
improvements in gain factor could be achieved.
substantial
One of the issues
presently being debated by the NEMC-MIT BNCT group is whether the
cranial BNCT protocol should involve single irradiation or multiple
fractions.
One frequently voiced argument favoring multiple fractions is
based on the assumption that the biological effectiveness of the low LET
dose component, which is principally the gamma dose, would be reduced
approximately by a factor of 2 relative to single fraction irradiation, and
thus increase the tumor selectivity of the dose.
However, the data points
in Figures 3.12 and 3.13, labelled "4 fractions," indicates that this would
produce a very small impact on the gain factors.
Figure 3.14 shows the contribution of the RBE weighted dose
components to the total tumor RBE dose at various depths along the central
axis of the epithermal neutron beam for tumor containing 40 ppm of
10 B.
For a midline tumor the fractional contributions of thermal neutron,
epithermal and fast neutron, gamma, and
22%, and 71%, respectively.
10B
physical doses are 2.4%, 4.4%,
From the NCTPLAN results it can be estimated
that at brain midline the structure-induced and core-gamma dose
components collectively account for approximately 60% of the total gamma
dose.
Therefore, if these, together with all the epithermal and fast neutron
dose, could be completely eliminated from the beam the percentage of
RBE dose would increase from 71% to approximately 84%.
It should be
emphasized that the gain factor and RBE dose component analysis as
52
10B
presented apply only to the M67 beam at MITR-II, and only for the
specifically defined cranial anatomy, and tumor size, shape, and location.
•,
,k:^•l-. "T'^•.-,I-
NJE-Mc-MIT
BNCT
Date: 6/95
Beam: M67/15
Orientation: P-C
Tumor PPM: 40
Normal PPM: 1
Normalization:
# Fractions : 1
Isodoses: Norm
RBE Set: BNL
100
~~*~;·"
Figure 3.8 Normal brain isodoses computed by NCTPLAN in transverse
plane through head of subject using lateral parallel-opposed irradiation
with the M67 epithermal neutron beam, as indicated by the arrows.
Assumed B-10 concentration is 10 ppm.
53
__
__
SlAIT DklMCT
.IvlIt I LYlC.,
Subject: Test
Date: 6195
Beam: M67/1 5 cr
Orientation: P-OTumor PPM: 40.(
Normal PPM: 10
Normalization: 2
# Fractions: 1
Isodoses: Tumor
RBE Set: BNL
Figure 3.9 Tumor isodoses computed by NCTPLAN in transverse plane
through head of subject using lateral parallel-opposed irradiation with the
M67 epithermal neutron beam, as indicated by the arrows. Assumed B-10
concentration is 40 ppm.
54
AC-MIT BNCT
Subject: Test
Date: 6/95
Beam: M67/15 cm
Orientation: P-O-P
Tumor PPM: 40.00
Normal PPM: 10.01
Normalization: 22.1
# Fractions: 1
Isodoses: Tumor
RBE Set: BNL
00
Figure 3.10 Normal brain isodoses computed by NCTPLAN in coronal
plane through head of subject (same subject and beam orientation as in
figure 8) using lateral parallel-opposed irradiation with the M67
epithermal neutron beam. Assumed B-10 concentration is 10 ppm.
55
__
Vl - I· __BNCT__
Subject: Test
Date: 6/95
Beam: M67/15 c
Orientation: P-O
Tumor PPM: 80.
Normal PPM: 2(
Normalization:
# Fractions: 1
Isodoses: Tumo
RBE Set: BNL
IV
C-MIT
BNCT
Figure 3.11 Tumor isodoses computed by NCTPLAN in a tranverse plane
through the head of a subject (same subject and beam orientation as in
Figure 3.8) using lateral parallel-oppoed irradiation with the M67
10 B concentrations are doubled to 20
epithermal neutron beam. Asuumed
ppm in normal brain and 80 ppm in tumor. A small midline tumor has
been "pasted" into the CT image. The isodoses are used to obtain the
"encompassing dose" that this tumor would receive; e.g., an encompassing
dose of 180% corresponds to gain factor of 1.8.
56
S400
300
200
100
°
C-
0
20
40
60
80
100
120
140
160
Tumor 1OB Concentration [PPM]
3.12 Gain-factor vs. 1 0 B concentration in tumor for three different 10 B
tumor-to-normal brain ratios of 3:1, 10:1, and 20:1. Most of the data
points are for an assumed gamma RBE of 1.0, corresponding to the delivery
of BNCT in a single fratcion; additional data points at 40, 80, and 120 ppm
10B assume a gamma RBE of 0.5, corresponding to the delivery BNCT in
four daily fractions.
57
__
600
I
500
p
I
I
I
I
I
I
I
I
I I
'
'
'
I
'
I
S-
-- 40 ppm
X
40 ppm /4Frac
--
-80 ppm
+
80 ppm /4Frac
-
- - 120 ppm
A
120 ppm /4 Frac
I
I
z
400
---
-_
-
300
o
-
"
200
100
U
0
5
10
15
20
25
' 0B Tumor-To-Normal Tissue Ratio
Figure 3.13 Gain-Factor vs. tumor-to-normal brain 10 B concentrations in
tumor of 40, 80, and 120 ppm. Most of the data points are for an assumed
gamma RBE of 1.0, corresponding to the delivery of BNCT in a single
fraction; additional data points at tumor-to-normal brain 10 B ratios of 3:1,
10:1, and 20:1 assume a gamma RBE of 0.5, corresponding to BNCT delivery
in four daily fractions.
58
I] Gamma
[IT
Fast N
B-10
Therm N
20
E
Cr_
(D
o0
!
cr
Cz
cr'
U)
0o
0
I-
0
1
2
3
4
5
6
Central Axis Depth [cm]
7
8
Figure 3.14 Percentage contribution of the individual RBE dose
components to total tumor RBE dose at various depths in the subject's head
(same subject as in Figure 3.8). Single fraction irradiation (i.e. RBE=1 for
gamma dose) is assumed. Tumor is assumed to contain 40 ppm of 10B.
59
3.5 Sample Treatment Plans of Human Subjects
This section gives examples of actual treatment plans of Three
subjects have completed the New-England Medical Center--Massachusetts
Institute of Technology phase-I boron neutron capture therapy doseescalation melanoma protocol. The tumor and normal tissue
10B
concentrations of patients V. A., G. H., and J. Y. represent intracellular
concentrations measured by High-Resolution Quantitative Autoradiography
(HRQAR) (see reference [6] for more on HRQAR) that was done on tissue
biopsies. Blood values were measured by prompt-gamma thermal neutron
activation analysis at the MIT Research Reactor. The blood samples and
punch biopsies of normal skin and tumor tissue were taken following a test
dose administration of BPA. Based on the results of a rapid
10 B
blood sample taken prior to an irradiation and the shape of the
assay of a
10B
blood
distribution curve the concentrations of boron in blood, tumor, and normal
tissue are determined. Table 3.2 summarizes the results obtained using
BNCTDOSE. Each entry represents the average
10B
concentration during
irradiation. HRQAR data for the first subject in the phase-II of the
melanoma protocol, P.D., is in the process of being calculated. An estimate
of 5.6 ppm blood boron concentration and a 3:1 ratio of tumor to normal
tissue boron concentration have been used for the purpose of this
treatment plan. These concentrations were inputed into NCTPLAN, the
Monte Carlo-based treatment planning software, and were used in the
calculation of various RBE-dose isocontours. The isocontours are
superimposed on the CT scans. The RBE's that were used are the same as
mentioned in section 3.1.2. Table 3.3 summarizes the total RBE doses that
subjects V.A., G.H., & J.Y. received. Both sets of isocontours, tumor and
normal tissue, are normalized to 95% of the maximum RBE-dose to normal
tissue (as described previously in this chapter).
Fraction #1
Fraction #2
Fraction #3
Fraction #4
2.4 ±0.2
2.5 ±0.2
2.0 ±0.1
2.2 ±0.1
Tissue
2.8 ±0.8
2.9 ±0.8
2.3 ±0.6
2.6 ±0.7
Tumor
8.5 ±1.1
9.0 ±1.1
7.1 ±0.9
7.9 ±0.9
Tumor/Norm
3.1 ±0.9
assumed the
same
Tumor/Blood
3.6 ±0.5
assumed the
same
Norm/Blood
1.2 ±0.3
assumed the
same
V.A.
G.H.
Blood
2.4 ±0.2
2.4 ±0.2
3.0 ±0.2
3.1 ±0.2
Tissue
2.7 ±0.6
2.7 ±0.6
3.5 ±0.8
3.6 ±0.8
Tumor
9.5 ±1.1
9.5 ±1.1
12.2 ±1.4
12.5 ±1.5
Tumor/Norm
3.5 ±0.9
assumed the
same
Tumor/Blood
4.0 ±0.6
assumed the
same
Norm/Blood
1.2 ±0.3
assumed the
same
J.Y.
Blood
Blood
3.3 ±0.2
5.5 ±0.3
5.3 ±0.3
7.1 ±0.4
Tissue
2.8 ±0.6
4.8 ±1.0
4.6 ±1.0
6.2 ±1.3
Tumor
7.8 ±1.0
13.3 ±1.6
12.7 ±1.6
17.1 ±2.1
Tumor/Norm
2.8 ±0.7
assumed the
same
Tumor/Blood
2.4 ±0.3
assumed the
same
Norm/Blood
0.9 ±0.2
assumed the
same
TABLE 3.2 : SUMMARY OF AVERAGE
10 B
CONCENTRATIONS [PPM] DURING
IRRADIATION IN BLOOD, NORMAL TISSUE, & TUMOR FOR BNCT SUBJECTS
V.A., G.H., & J.Y.
Dose (RBE-cGy)
V.A.
G.H.
J.Y.
Blood
1001
1001
1001
Normal Tissue
1021
1027
947
Tumor*
1317
1512
1389
TABLE 3.3 : TOTAL ACTUAL RBE DOSES DELIVERED TO BNCT SUBJECTS
V.A., G.H., & J.Y.
SUBJECT V. A.
Subject V.A. presented at the Boston City Hospital with a melanoma
of the plantar surface of the right foot. CT scans of the head, neck,
abodomen, chest and pelvis were negative and the subject was judged in
good health with the exception of the melanoma lesion on the sole of his
foot. RBE-dose isocontours were calculated for the transverse plane
through the foot, through the central axis of the circular 15 cm diameter
neutron beam, approximately mid-way between the toe and the heel. Both
normal tissue (Fig. 3.19) and tumor (Fig. 3.20) dose isocontours were
calculated. Dose isocontours were also calculated for the sagital plane (Fig.
3.21, Fig. 3.22) through the center of the foot, and for transverse slices 25
mm on either side of the beam center (Figs. 3.23-3.26). The results show
that in all of the above slices the maximum dose to tumor is 120% of the
maximum dose to normal tissue. As expected, the dose doesn't change
significantly between the above transverse slices. See Figure 3.15 for the
locations of the nodules and corresponding calculation planes.
62
SUBJECT G. H.
Subject G.H. came to the NEMC following several excisions of a
melanoma of the lower left leg. Subject G.H. noticed two subcutaneous
metastatic lesions on the lower left leg and decided to enter the NEMC-MIT
BNCT phase-I trial. CT examinations of the chest, abdomen, and pelvis
revealed no evidence of any other metastatic disease. Figures 3.27 and
3.28 show normal tissue and tumor dose isocontours drawn on a
transverse CT section located 42 mm inferiorly from the center of the
beam. The small nodule at the top of Figure 3.29 received between 80% to
110% of the maximum dose to normal tissue. Figures 3.30 and 3.31 show
dose isocontours drawn on a transverse CT section located 75 mm
inferiorly from the center of the beam. The large nodule that is located at
the upper right hand side of Figure 3.32 received between 30-70% of the
maximum dose to normal tissue. This low Figure is because the nodule is
in the penumbral region of the neutron beam. Figure 3.16 depicts the
lower left leg of subject G.H.
SUBJECT J. Y.
Subject J.Y. came to the NEMC-MIT BNCT trial after several excision
attempts to remove a discolored mole on the skin of the lower left leg
failed. Declining amputation, subject J.Y. became the third subject of the
phase-I trials at NEMC-MIT. A work-up for distal metastases in the chest,
abdomen, and pelvis was negative. Three nodules were detected on the CT
scans superiorly to the center of the beam. Figures 3.33 and 3.34 are dose
isocontours superimposed on a transverse CT section, 34 mm superiorly
from the beam center. One nodule is located at the left of the Figure and
one at the top. Figure 3.35 shows that the left nodule received between
65-95% of the total dose to normal tissue. It is hard to determine from
Figure 3.36 what dose the nodule at the top of the CT scan received
because of the isocontour artifact. An estimate would yield 80-95% of the
total dose to normal tissue. Figure 3.37 shows normal tissue dose
isocontours drawn on a CT scan that is 40 mm superiorly to the center of
the beam. Figure 3.38 shows the same CT scan with tumor tissue dose
isocontours drawn. From Figure 3.39 it is possible to estimate the dose to
the nodule at the upper right corner as being between 115-130% of the
total dose to normal tissue. Figure 3.17 illustrates subject J.Y.'s lower left
leg.
SUBJECT P.D.
Subject P.D. is the first subject at the second dose-escalation level of
the melanoma protocol which increases the dose to normal tissue to 1250
RBE-cGy. Subject P.D. has a single small nodule visible at the inner part of
her right leg, located a few millimiters above the knee line. An estimate of
5.6 ppm for the normal tissue boron concentration was obtained from the
test dose boron blood curve. Consequently, a 16.8 ppm boron
concentration was used in calculating the tumor dose isocontours
(assuming a 3:1 ratio). Figure 3.40 shows normal tissue dose isocontours
drawn on a transverse CT slice through the central axis of the beam. Figue
3.41 shows the tumor tissue dose isocontours drawn on the same CT scan.
Although the nodule is not visible on the CT scan, Figure 3.42 yields an
estimate for the dose received by the nodule of 100-125% of the maximum
dose to normal tissue. The location of the nodule can be determined from
Figure 3.18.
CONCLUSION
Three subject, V.A., G.H., and J.Y., have completed the NEMC-MIT
BNCT phase-I melanoma protocol. There was clear partial response of the
melanoma nodules within the irradiation field in two out of the three
subjects. The low therapeutic ratio of approximately 30% higher RBE-dose
to tumor than to normal tissue can be attributed to the low concentrations
of boron in tumor tissue and to the suboptimal beam orientations for
maximizing this ratio since the primary purpose was to obtain a well
defined area of normal tissue receiving a well defined RBE-dose. This
concentration ranged from 10.8 ppm for subject V.A. to 12.1 ppm for
subject G.H..
;ntral Axis
E
CD]
Figure 3.15. Subject V.A.'s right foot
25mm
dline slice
wn 25mm
dules
Beam Width
nodule 1
i
Figure 3.16. Subject G.H.'s lower left leg
I
Beam
nodule 2
nodule
Figure 3.17. Subject J.Y.'s lower left leg
nodule
Central Axis
re-wi fin
m Center
Beam Width
Figure 3.18. Subject P.D.'s right leg
69
Patient: V.Adam
Date: 7/95
Beam: M6711 5cm
Orientation: PRI
Tumor PPM: 11.51
Normal PPM: 3.74
Normalization: 7.62
# Fractions: 4
Isodoses: Normal
RBE Set: MIT
NEMC-MIT BNCT
10
Figure 3.19. Subject V.A. normal tissue dose isocontours for a transverse
plane through the foot.
Patient: V.Adam
Date: 7195
NEMC-MIT BNCT
RBAm: M"R7, 1 r nm
Ori entati
Tumor P
NormnalP
Normaliz
# Fracti(
Isodose
RBE Sel
Figure 3.20. Subject V.A. tumor tissue dose isocontours for a transverse
plane through the foot.
Patient: V.Adam
Date: 7/95
Beam: M67/1 5cm
Orientation: PR I
Ti imnr DDMA- 11 c1
Figure 3.21. Subject V.A. normal tissue dose isocontours for a sagital
plane through the foot.
NEMC-MIT BNCT
Patient: V.Adam
I-Ml •
?JQOE
Figure 3.22. Subject V.A. tumor tissue dose isocontours for a sagital plane
through the foot.
NEMC-MIT BNCT
Patient: V.Adam
Date: 7/95
Beam: M6711 5cm
Orientation: PRI
Tumor PPM: 11.51
Normal PPM: 3.74
Normalization: 7.62
# Fractions: 4
Isodoses: Normal
RBE Set: MIT
Figure 3.23. Subject V.A. normal tissue dose isocontours for a transverse
plane through the foot, 25 mm inferiorly to the center of the beam.
NEMC-MIT BNCT
Normal PPM: 3.74
Normalization: 9.22
ns: 4
Patient: V.Adam
Date: 7/95
Bean
Orier
Tum(
: Tumor
:MIT
NEMC-MIT BNCT
Figure 3.24. Subject V.A. tumor tissue dose isocontours for a transverse
plane through the foot, 25 mm inferiorly to the center of the beam.
Patient: V.Adam
Date: 7/95
Beam: M67/1 5cm
Orientation: PRI
Tumor PPM: 11.51
Normal PPM: 3.74
Normalization: 7.62
# Fractions: 4
Isodoses: Normal
RBE Set: MIT
NEMC-MIT BNCT
4n
Figure 3.25. Subject V.A. normal tissue dose isocontours for a transverse
plane through the foot, 25 mm superiorly to the center of the beam.
Patient: V.Adam
Date: 7195
Tumor PPM: 11.51
Normal PPM: 3.74
ation: 9.22
ns: 4
3: Tumor
Or
RI
I
•
L.IYN~...VII I
UI'-. I
Figure 3.26. Subject V.A. tumor tissue dose isocontours for a transverse
plane through the foot, 25 mm superiorly to the center of the beam.
Patient: G. Hinz
Date: 7/95
Beam: M67/1 5cm
Orie ntation: PRI
Tumor PPM: 12.07
Norr
Norr
# Frc
Isod,
RBE
i
,, ,•L ,
•
,
Figure 3.27. Subject G.H. normal tissue dose isocontours for a transverse
plane through the foot, 42mm inferiorly to the center of the beam.
NEMC-MIT BNCT
Figure 3.28. Subject G.H. tumor tissue dose isocontours for a transverse
plane through the foot, 42mm inferiorly to the center of the beam.
Patient: G. Hinz
Date: 7/95
Beam: M67 115cm
Orientation: PR I
Tumor PPM: 12.07
NEMC-MIT BNCT
Figure 3.29. Small nodule at the top - subject G.H. tumor tissue dose
isocontours for a transverse plane through the foot, 42mm inferiorly to the
center of the beam.
Normal PPM: 3.45
Normalization: 10.02
# Fractions: 4
Isodoses: Tumor
0DED C-CI- Kc IT
IYII I
Patient: G. Hinz
Date: 7195
Beam: M6711 5cm
Orientation: PRI
Tumor PPM: 12.07
Normal PPM: 3.45
KlIn'IIli-?
ih n- 7 d4
# Fra
Isodc
RBE
Figure 3.30. Subject G.H. normal tissue dose isocontours for a transverse
plane through the foot, 75 mm inferiorly to the center of the beam.
NEMC-MIT BNCT
Patient: G. Hinz
Date: 7/95
Beam: M67/1 5cm
Orientation: PR I
Tumor PPM: 12.07
Normal
PPM: 3.45
SI•L'..%•.I :-I-J"I:^L",." 4 A rI""
IfV
# Fr
Isoc
RBE
Figure 3.31 Subject G.H. tumor tissue dose isocontours for a transverse
plane through the foot, 75 mm inferiorly to the center of the beam.
NEMC-MIT
Patient: G. Hinz
Date: 7/95
Beam: M67 11 5cm
Orientation: PR I
Tumor PPM: 12.07
Normal PPM: 3.45
•_m_
' __
u- . .
.
NEMC-MIT BNCT
,',,•
^, ^
Nonr
# Fr
Isod
RBE
Figure 3.32 Nodule at the upper right hand side - subject G.H. normal
tissue dose isocontours for a transverse plane through the foot, 75 mm
inferiorly to the center of the beam.
Patient: J. Young
Date: 7195
Beam: M67/1 5cm
Orientation: PRI
Tumor PPM: 10.78
Normal PPM: 3.91
Normalization: 7.22
# Fractions: 4
Isodoses: Normal
RBE Set: MIT
Figure 3.33 Subject J.Y. normal tissue dose isocontours for a transverse
plane, 34 mm superiorly to the center of the beam.
NEMC-MIT BNCT
Patient: J. Young
Date: 7/95
Beam: M671 15cm
Orientation: PRI
Tumor PPM: 10.78
Normal PPM: 3.91
Normalization: 9.1 6
# Fractions: 4
Isodoses: Tumor
RBE Set: MIT
Figure 3.34 Subject J.Y. tumor tissue dose isocontours for a transverse
plane, 34 mm superiorly to the center of the beam.
NEMC-MIT BNCT
NEMC-MIT BNCT
Patient: J. Young
Date: 7/95
Beam: M671 15cm
Orientation: PRI
Tumor PPM: 10.78
Normal PPM: 3.91
Normalization: 9.1 6
# Fractions: 4
Isodoses: Tumor
RBE Set: MIT
Figure 3.35 Noduel on left hand side - subject J.Y. tumor tissue dose
isocontours for a transverse plane, 34 mm superiorly to the center of the
beam.
86
Patient: J. Young
Date: 7/95
Beam: M671 15cm
Orientation: PRI
Tumor PPM: 10.78
Normal PPM: 3.91
Normalization: 9.16
# Fractions: 4
Isodoses: Tumor
RBE Set: MIT
Figure 3.36 Nodule at the top - subject J.Y. tumor tissue dose isocontours
for a transverse plane, 34 mm superiorly to the center of the beam.
NEMC-MIT BNCT
Patient: J. Young
Date: 7/95
Beam: M67/1 5cm
Orientation: PRI
Tumor PPM: 10.78
Normal PPM: 3.91
Normalization: 7.22
# Fractions: 4
isodoses: Normal
RBE Set: MIT
Figure 3.37 Subject J.Y. normal tissue dose isocontours for a transverse
plane, 40 mm superiorly to the center of the beam.
NEMC-MIT BNCT
Patient: J. Young
Date: 7195
Beam: M671 15cm
Orientation: PR I
Tumor PPM: 10.78
Normal PPM: 3.91
Normalization: 9.1 6
# Fractions: 4
Isodoses: Tumor
RBE Set: MIT
Figure 3.38 Subject J.Y. tumor tissue dose isocontours for a transverse
plane, 40 mm superiorly to the center of the beam.
NEMC-MIT BNCT
NEMC-MIT BNCT
Patient: J. Young
Date: 7/95
Beam: M6711 5cm
Orientation: PRI
Tumor PPM: 10.78
Normal PPM: 3.91
Normalization: 9.1 6
# Fractions: 4
Isodoses: Tumor
RBE Set: MIT
Figure 3.39 Nodule at the upper right hand side - subject J.Y. tumor
tissue dose isocontours for a transverse plane, 40 mm superiorly to the
center of the beam.
90
Patient: P. Davin
Date: 10195
Beam: M67/1 5cm
Orientation: PRI
Tumor PPM: 16.80
Normal PPM: 5.60
Normalization: 8.04
# Fractions: 4
Isodoses: Normal
RBE Set: MI
Figure 3.40 Subject P.D. normal tissue dose isocontours for a transverse
plane through the center of the beam.
NEMC-MIT BNCT
Patient: P.Davin
Date: 1095
Beam: M67/1 5cm
Orientation: PR I
Tumor PPM: 16.80
Normal PPM: 5.60
Normalization: 11.35
# Fractions: 4
Isodoses: Tumor
RBE Set: MI
Figure 3.41 Subject P.D. tumor tissue dose isocontours for a transverse
plane through the center of the beam.
NEMC-MIT BNCT
Patient: P.Davin
Date: 10/95
Beam: M67/1 5cm
Orientation: PR I
Tumor PPM: 16.80
Normal PPM: 5.60
Normalization: 11.35
# Fractions: 4
Isodoses: Tumor
RBE Set: MI
NEMC-MIT BNCT
Figure 3.42 Nodule not visible - subject P.D. tumor tissue dose
isocontours for a transverse plane through the center of the beam.
93
Chapter 4 Beam Monitoring System
4.1 Description of the Existing System
An epithermal neutron beam has been constructed and used for
research and clinical trials at the MIT Research Reactor. The MITR-II
medical beam, incident upon the patient, is principally comprised of either
epithermal or thermal neutrons. Undesirable contaminants of thermal
neutrons, fast neutrons, and gamma rays are also present in the beam and
must be accounted for in the dosimetry. In tissue, the epithermal neutrons
are rapidly thermalized and these slow neutrons are absorbed in
produce the 10B(n,
a) 7 Li capture reaction. The
have a combined range in tissue of about 13
10 B
to
a-particles and the Li ions
u m, a total kinetic energy of
2.3 MeV, and can be highly lethal to tumor cells if located in the vicinity of
their nuclei.
The complexity BNCT Dosimetry relative to conventional
radiotherapy has been illustrated by Figure 1.1, which provides the dose
versus depth for all major components in a BNCT type irradiation. A tumor
10 B
concentration of 30 ppm and a healthy tissue
10 B
concentration of 7.5
ppm are assumed for this computation. These levels of boron are
reasonable examples of what is actually attainable in vivo for a boron
delivering compound such as boronated phenylalanine.
A beam monitoring system helps assure that the specified patient
dose is delivered to the patient within acceptable dose tolerances of the
target dose. Our approach to meeting the desired dose tolerances has
included the development of a beam monitoring system which monitors
and provides on-line display of the fluence of epithermal and thermal
neutrons and which monitors the beam characteristics, e.g. energy
distribution and spatial distribution, and indicates if these are stable
(within a certain percentage specified by the user) during the irradiation.
The beam monitoring system also indicates any changes in beam
characteristics from those which existed when the beam was fully
dosimetrically characterized and calibrated. The beam monitoring system,
including the radiation detectors, the readout and display system,
procedures for calibration, and the performance of the entire beam
monitor system are discussed in some detail in another paper [
29],
brief description of the hardware will be presented here. Further details
concerning the beam monitor system are found in two MIT masters' theses
0 31].
The epithermal neutron beam size is determined by a beam
delimiter. The current size is 15 cm in diameter. Various beam detectors
have been examined for sensitivity, size (need to be small as to not to
perturbe the beam) and cost. Two fission counters, manufactured by TGM
were selected to monitor epithermal neutrons. Since these are quite
sensitive to thermal neutrons too, the two detectors were covered with
thermal neutron-absorbing 6Li 2CO 3 . An unshielded fission counter or a 3He
ionization chamber are used to monitor the thermal neutron flux. In order
to monitor the gamma ray flux, a high-pressure argon gas filled detector is
used. These detectors are quite small (a few centimeters in diameter and
length), so that when placed at the edge of the beam they have a negligble
effect on the beam uniformity and strength. By choosing these various
detectors and placing them strategically around the beam [1], it is possible
95
so only a
to monitor the intensity, coarse energy spectrum and spatial distribution of
the beam.
The fission counters have their signals passed through a data
acquisition board in a Mac IIci computer, and the current mode detectors
are first converted to a proportional frequency signal and then passed to
the computer. These signals are also recorded on scalars, which can be
read manually, for backup. Thus, any failures of the computer-based
system (such as power supply failure on the computer) will not result in
a loss of the most important data. In addition, several reactor power
monitors are used as an independent monitoring system since there is a
measureable correlation between reactor MW-minutes and epithermal
neutron fluence.
The computer uses an application of the data acquisition and
processing program called LabVIEW 2® [
32] to display on a 17" color
monitor the detector count rates, integral counts, dose calibration factors,
target counts, percentage of target counts, and irradiation time. The front
panel display of the LabVIEW 2® Beam Monitor Virtual Instrument (VI) is
shown in Figure 4.1. The Beam Monitor VI is presented in more detial in
the following section.
96
Mrad Annm
Figure 4.1. A typical screen display of the beam monitor virtual
instrument provides count rates, integral counts, corresponding doses,
target counts and doses, and irradiation time. These are displayed, color
coded, in digital and analog modes. Additional information such as patient
identification information is also displayed on the monitor.
4.2 Software Implementation
An application program that was created using LabVIEW 2 0 is called
the beam monitor virtual instrument (VI). It consists of three main parts:
the front panel, the block diagram, and the icon/connector. The block
diagram is a VI's source code, which is created using a graphical
programming language called G. The front panel is the user interface to
mmI Pannal
the VI, and the icon/connector together represent the VI in a manner
analogous to a subroutine call statement when the VI is used as a subVI in
another VI's block diagram (not used in our case). Detector output is
shown in digital as well as in analog form, color coded to each separate
detector. The analog display in relative count rates on the lower left hand
side of Figure 4.1 is designed for ease in rapidly diagnosing any significant
changes or trends in the energy, spatial distribution, and intensity of the
beam. The bar graph on the lower right hand side of the screen with an
analog display showing the percent of target detector counts is particularly
useful in determining when the target dose is approached. Above the
latter bar graph, target counts, integrated counts and percent target are
also shown in digital form. An average of the epithermal detector outputs
is also calculated by the computer and this is displayed in analog form as
percent of target dose near the upper right hand part of the monitor. An
audible signal is provided when the target dose, based on averaged
epithermal neutron counts, is reached. The information on the monitor is
typically updated every 5 seconds, although this can be set to any desired
interval by the programmer. This monitor display also shows the patient
hospital identification number, name, and the dose calibration factors, i.e.
epithermal counts per RBE-cGy. A magnetic disk record is made of the
information displayed by the computer. Each patient has a separate floppy
disk record of his or her irradiation. A start/pause, reset, and status check
control panel are located in the upper left hand part of the monitor
display.
A separate monitor provides additional information on the beam and
the irradiation (see Figure 4.2). At the top left hand side of the display
there are virtual switches that can be used to turn off an epithermal
98
neutron beam monitor, e.g. if a beam monitor becomes erratic. The two
epithermal beam monitors are used to control the length of the irradiation
since the dose that needs to be delivered for this kind of therapy is
primarily determined by the epithermal neutron fluence or dose.
However, if one monitor should become unreliable, for any reason, this
monitor could be turned off and the remaining monitor would be used to
control the irradiation. On the left
Figure 4.2. A separate screen display provides reactor power and beam
monitor count rates compared to reference values. The display is shown
on a separate monitor and presents the preset percent deviation of the
epithermal monitor counts which will trigger an alarm, and the ratios of
the various beam monitor count rates which provide useful information on
beam symmetry and relative energy. In addition, on/off switches which
can eliminate data from an epithermal beam monitor are highlighted in
red.
99
hand side of the display, the reactor power planned for a specific fraction
and the actual beam monitor count rates are displayed along with the
expected, or reference, power and count rates. At the top right hand side
the maximum preset percent deviation which will be allowed before and
alarm is triggered is displayed. Below that are the ratios of all the beam
monitor count rates, including the statistical error on the ratios. The latter
information provides numerical indicators for beam symmetry, relative
beam energy, and relative gamma ray intensity. Any variation in these
ratios from the reference ratio by more than a user preset percentage
(typically set at 10%), produces an alarm indication on the check status
light shown on the upper left hand part of the monitor display in Figure
4.2.
4.2.1 BNCTDose - Purpose and Use
A program has been written in MathCAD® to facilitate dose
calculations. The original MathCAD® based dose calculation is called
BNCTDose, whereas the new implementation is called BNCTDoseVI from
hereon. BNCTDose takes as its inputs the irradiation start interval (the
time interval subsequent to the administration of Boronphenylalanin), the
pre-irradiation
10 B
blood concentration interval along the test
10B
blood
uptake curve (corresponding to tissue biopsy time). Other dosimetric and
experimental beam monitor calibration parameters are also inputed into
the MathCAD® module for the purpose of updating whenever beam
modifications are done - these inputs need not be updated at every
irradiation. The user starts by inputting the desired maximum dose to
normal tissue. The program normalizes this figure against the Monte Carlo
100
dose rate ratio that has been measured in the phantom calibration. The
integral of the total dose from the four different dose components (fast
neutrons, thermal neutrons,
Y, and 10B) is calculated by MathCAD®
everytime it is executed.
During a typical irradiation the blood
10B
concentration changes and
this factor needs to be accounted for when target beam monitor-count
calculations are performed. Originally, this meant that the user needed to
look at the blood concentration vs. time curve and decide what the current
blood concentration is at that point of the irradiation. One of the current
modifications of BNCTDoseVI is the automation of this process of
determining blood
10B
concentration from a fit to the empirical data.
4.2.2 LabVIEW 2®
LabVIEW 2® is a data acquisition and processing software that is
used to create applications that are called virtual instruments (VIs). The
application programs Beam Monitor BNCTDoseVI is comprised of two main
parts: the front panel (Figure 4.3) and the block diagram (Figure 4.4). The
block diagram will be wired and inserted in the beam monitor VI
sequence. A seqence structure, which looks like a frame of film, consists of
one or more subdiagrams, or frames, that execute sequentially. The latest
beam monitor VI implementation consists of 16 main sequences,
numbered from 0 to 16. This facilitates the control flow, the order of
execution of the program. The data flows from frame 0 to the last frame.
The first few frames control the resetting of various counters and
recording of patient information. A radiation timer is implemented in the
second frame and the virtual beam counters are connected to the data
101
acquisition processing board. The flow of operation is more easily seen on
the schematic, but it's size prohibits its addition to this work.
The best ways to modify the existing system by the creation of an
independent virtual instrument, such as the BNCTDoseVI. This VI can be
debugged and tested separately before wiring it to the existing beam
monitor VI diagram. In this way, the existing system can still operate
without the new modifications. It is quite difficult to wire the additional
sequence correctly, in the right order, so extra care needs to be taken.
Backups of the working beam monitor application exist in case the
modified version does not work.
4.3 Integration of NCTPLAN results and BNCTDose into
the Beam Monitoring Software LabVIEW 2®
The previous beam monitor virtual instrument has been modified to
eliminate the need for the use of BNCTDose (a MathCAD® based dose
calculating program), and KaleidaGraphTM for fitting an exponential of a
predetermined shape to the blood uptake curve. The purpose of
KaleidaGraphTM was to determine the instantaneous blood concentration
during an irradiation. The programs were setup in the following way:
* A test dose of the therapeutic agent is administered and fifteen blood
10B concentration versus time data points are collected prior to
administration.
* These fifteen points are fitted to a double exponential curve using the
program KleidaGraph and a blood 10 B concentration vs. time uptake
curve is obtained.
* A pre-irradiation 10B blood concentration level is determined and the
blood uptake curve is scaled accordingly.
102
* The scaled concentration at the start of irradiation is inputted into
BNCTDose to determine the estimated irradiation length and the
calculated epithermal and thermal monitor units that need to be
obtained in order to deliver the specified epithermal neutron dose.
* Every few minutes the blood concentration value is determined and is
re-inputted into BNCTDose to yield a new estimated irradiation length
and new targets for monitor unit counts.
* The last step is repeated several times during an irradiation to obtain a
delivered dose that is as close to the target dose as possible. This
process is quite accurate, but tedious and its automation was a vital
step in insuring both an accurate and rapid dose delivery in future
irradiations.
The solution to the problem of repeated dose calculation is to automate it
and incorporate the blood uptake curve and the BNCTDose calculations into
LabVIEW 2®.
To simplify the task of programming and debugging a new virtual
instrument called BNCTDoseVI has been created with the intention of
wiring it to the existing beam monitor virtual instrument as a frame in the
existing sequence structure. A front panel for the BNCTDoseVI that
consists of all the inputs and outputs of BNCTDose has been created (see
Figure 4.3). These inputs include the irradiation start interval (the time
interval subsequent to the administration of Boronphenylalanin), the preirradiation
10B
blood concentration interval along the test
10 B
blood uptake
curve (corresponding to tissue biopsy time), and other inputs, such as
reactor power, that will later be linked to existing beam monitor panel
inputs (i.e., reactor power is a redundant input created solely for the
purpose of testing the virtual instrument). Other dosimetric and
experimental beam monitor calibration parameters are also shown in the
front panel for the purpose of updating whenever beam modifications are
103
done - these inputs need not be updated at every irradiation. The front
panel also includes digital indicators for the various parameters that
BNCTDoseVI calculates in its operation. Again, these indicators are used
primarily for identifying problems that might arise in operation. Some of
these indicators will be directly wired to the existing beam monitor virtual
instrument (i.e., EBCF1 and EBCF2 - the experimental beam calibration
factors) and some will remain for future reference (i.e. MPDRtotal, the
indicator for the calculated average dose rate in patient).
The design of the front panel has been deliberately made compact so
as to save space on the monitor screen. The current design easily fits in a
15" monitor unit, and with minor modifications, could be made to fit on the
separate monitor that is used for additional information. Though, when
the visual display of the fitted blood uptake curve will be included a
separate monitor will need to be purchased for better clarity.
All the dose calculations that were originally part of BNCTDose have
been transformed to LabVIEW 2@ format, the BNCTDoseVI, using the G
visual programming language. A part of the schematic of the program is
enclosed at the end of this chapter for reference (Figure 4.4). A summary
of the different controls and indicators and a description of each is also
found at the end of this chapter. Figure 4.3 shows an example of the
modified BNCTDoseVI front panel.
104
BNCTDoseUI Panel
Figure 4.3 The BNCTDoseVI front panel provides several important
results that are later used in the beam monitor VI. These include EBCF1,
EBCF2 - the experimental beam calibration factors, and target monitor unit
counts.
105
Figure 4.4 A portion of the BNCTDoseVI schematic diagram.
106
Description of the different controls and constants that
are used in BNCTDoseVI
Inputs
MDNT: Maximum Dose to Normal Tissue for this fraction.
BLCurveInterv: Interval along test 10B Blood curve - corresponding to
tissue biopsy time.
IrrStInterv:Estimated irradiation start interval - interval after BPA
administration.
BlDrawInterv: Pre-irradiation blood draw interval - interval after BPA
administration.
BloodConc: Pre-irradiation 10 B blood concentration.
ReactorPower: Estimated neutronic reactor power.
MCDR phantom: Monte Carlo Dose Rate in phantom at maximum dose
point along central axis and 7.5ppm.
MCDRpat_max: Monte Carlo Dose Rate in patient at maximum dose point
and 7.5ppm.
MCDR-pat_CA: Monte Carlo Dose Rate in patient at 2cm point along central
axis and 7.5ppm.
Results
EstIrrLength: Estimated Irradiation Length.
B_avg: Estimated averge 10 B concentration.
B_avgtest: Test dose average 10B concentration.
EBCFI: Experimental Beam Calibration Factor "EBCF1".
EBCF2: Experimental Beam Calibration Factor "EBCF2".
MCDRR: Monte Carlo Dose Rate Ratio.
MUl_calc: Calculated Monitor Units for Epi #1.
MU2_calc: Calculated Monitor Units for Epi #2.
MU_thl: Calculated Monitor Units for Th #1.
MU_th2: Calculated Monitor Units for Th #2.
MU_G: Calculated Monitor Units for Gamma.
BICurveValue: Test dose 10B concentration at BlCurveInterv.
InitialBlO_conc: 10B concentration at the beginning of therapy.
Final_Bl10conc: 10 B concentration at the end of therapy.
MPDR: Estimated average dose rate at peak dose point in patient with
B_avg.
DR_total: Measured Dose rate at 2cm on central axis in phantom with
7.5ppm 10B concentration.
107
108
Chapter 5 Summary and Conclusions
5.1 Summary
The aim of this work is to facilitate the use of the treatment planning
procedure at the New England Medical Center--Massachusetts Institute of
Techonology joint program in boron neutron capture therapy through an
improvement to the beam monitoring software and the documentation of
the other steps involved in a treatment plan. A detailed description of the
existing Monte Carlo based software, NCTPLAN, is presented with examples
of its various capabilities. Also, the treatment plans of four subject that
have been irradaited at the MITR-II research reactor are shown. The
treatment planning procedure has been modified over the past year and a
half as new difficulties arose. This
work presents the treatment planning procedure that is in effect for
December of 1995. More modifications are being done and a more user
friendly Macintosh-based program will eventually replace the current
VAX/VMS-based program. The modifications to the beam monitoring
software have not been completed due to technical difficulties that were
encountered over the past two
months. They will be completed in the next few weeks.
5.2 Recommendations for Future Work
As was mentioned in the previous section, more modifications to the
beam monitoring software need to be done. These will be completed in the
109
near future. Also, a Macintosh-based replacement for NCTPLAN is in the
making. That is also expected to be completed within a few months. The
Macintosh based system will enable eaier and faster manipulations of
images using such programs as NIH Image and Adobe Photoshop.
As of now, one of the biggest obstacles for an effective treatment
plan is computational speed of the Monte Carlo simulations. The
simulations for the last subject irradiated took on the order of a dozen
hours. New, faster computers can cut down the computation times to an
estimated hour. These computers are currently being purchased and
tested.
110
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12
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