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Research Reactor Users' Networks (RRUNs):

Advances in Neutron Therapy

Report of the IAEA Technical Meeting (F1-TM-44771)

Mainz, Germany, 1–4 July 2013

IAEA, Vienna, Austria

May 2014

NOTE

The material in this document has been supplied by the authors and has not been edited by the IAEA.

The views expressed remain the responsibility of the named authors and do not necessarily reflect

those of the government(s) of the designating Member State(s). In particular, neither the IAEA nor

any other organization or body sponsoring this meeting can be held responsible for any material

reproduced in this document.

CONTENTS

1. Background ............................................................................................................................... 1

2. Objectives of the meeting ......................................................................................................... 2

3. Work done ................................................................................................................................. 2

4. Summary of the main findings .................................................................................................. 4

4.1 Status of neutron therapy facilities ......................................................................................... 4

4.2 Boron and gadolinium uptake, control and time dependence .............................................. 12

4.3 Clinical trial protocols and reporting of doses ..................................................................... 17

4.4 Clinical results of BNCT and FNT ...................................................................................... 19

4.5 Point of view by the medical community ............................................................................. 23

4.6 Economic aspects ................................................................................................................. 25

4.7 Public acceptance ................................................................................................................. 27

5. Executive summary ................................................................................................................. 28

References ...................................................................................................................................... 30

Appendix I. List of participants ...................................................................................................... 31

Appendix II. Meeting agenda ......................................................................................................... 32

Appendix III. Book of abstracts ..................................................................................................... 37

1. IAEA, Ridikas ....................................................................................................................... 37

2. Argentina, Boggio ................................................................................................................. 38

3. Austria, Blaickner ................................................................................................................ 39

4. Brazil, Siqueira ..................................................................................................................... 40

5. Brazil, D’Agostino-Butantan ............................................................................................... 41

6. China, Li (not presented) ..................................................................................................... 42

7. Czech Republic, Klupak ...................................................................................................... 43

8. Germany, Al-Nawas ............................................................................................................. 44

9. Germany, Ross ...................................................................................................................... 45

10. Germany, Hampel ................................................................................................................ 46

11. Germany, Nawroth ............................................................................................................... 48

12. Germany, Wittig ................................................................................................................. 49

13. Germany, Sauerwein-1 ...................................................................................................... 50

14. Germany, Sauerwein-2 ...................................................................................................... 51

15. Germany, Wagner .............................................................................................................. 53

16. Germany, Specht ................................................................................................................ 54

17. Indonesia, Sardjono ........................................................................................................... 56

18. Italy, Altieri ......................................................................................................................... 57

19. Italy, Gambarini ................................................................................................................. 58

20. Japan, Matsumura ............................................................................................................. 59

21. Japan-Tokyo, Itami ............................................................................................................ 60

22. Japan, Ono .......................................................................................................................... 61

23. Poland, Gryzinski ............................................................................................................... 62

24. Russian Federation, Golovkov .......................................................................................... 63

25. Russian Federation, Lipengolts ......................................................................................... 64

26. United Kingdom, Schütz .................................................................................................... 65

27. USA, Kroc (video recorded) ................................................................................................ 66

28. USA, Fermilab, Welsh (not presented)............................................................................. 67

29. USA, Emery ......................................................................................................................... 68

IAEA TM on Use of Advances in Neutron Therapy; Mainz, Germany, 1-4 Jul. 2013

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1. BACKGROUND

Traditionally neutron beams have enjoyed a long history in advancing diverse research related to

materials study, structural examination and testing and basic neutron science among other areas,

and are uniquely created by research reactors and accelerator based neutron sources. Along with

radioisotope production, neutron transmutation doping of silicon, neutron activation analysis,

nuclear education and training programmes, neutron beams today stand as an additional

important factor in the R&D agenda of research reactors.

One of the neutron beam applications, less frequently promoted and known is neutron medical

treatment or neutron therapy. The property of neutrons that differentiates this therapy from more

conventional radiation therapy techniques like high energy X ray, electron or high energy proton

treatment is their ability to damages cells using so called high linear energy transfer (LET). This

is achieved by creation of secondary recoil protons and alpha particles, which distinguish two

branches of neutron therapy, fast neutron therapy (FNT) and boron neutron capture therapy

(BNCT), respectively.

The mean neutron energies used for the FNT range from 2 MeV to a few tens of MeV. These

neutrons are produced mainly by particle accelerators or compact neutron generators through

proton or deuteron induced reactions like 9Be(p,d)

8Be or

3H(d,n)

4He. In a few cases also

252Cf

neutron sources are employed. Fission of uranium induced by reactor thermal neutrons is another

way to produce fast neutrons with a mean energy of ~2 MeV. Based on more recent surveys,

FNT has been administered to about 30 000 patients worldwide, and 5 facilities continue to

operate (4 accelerator based and 1 reactor based). With curative intention, presently FNT is used

to treat prostate and lung cancer, adenoid-cystic carcinoma of head and neck, especially of the

major salivary gland tumours, breast and in some cases also thyroid cancers.

BNCT is based on thermal or epithermal neutron beams produced at research reactors. It was

initially developed for treatment of extremely aggressive forms of brain cancer, for which boron

compounds are injected in order to selectively damage only tumour cells through (n,α) reactions.

Another field of application in which BNCT has been tried is malignancies of skin and also head

and neck tumours. Although clinical results indicate significantly increased survival times, the

outcome has been palliative only, and the total number of patients treated by the BNCT remains

below 1000 with three-fourths of all patients administered in 3 research reactors, namely FiR-1 in

Finland and KUR & JRR4 in Japan.

In both neutron therapies mentioned above neutrons are delivered in mixed neutron and gamma

fields resulting in some unavoidable secondary reactions. In this context, biological dosimetry

continues to be a challenging field of research. Techniques used today are neutron fluence

monitors as activation foils in combination with paired ionization chambers. The resulting

measurements of total dose values and various contributors to the dose still need to reduce

uncertainties down to a level of 10% or less. Many groups around the world are therefore


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working on different approaches to improve experimental devices and associated methodologies.

In addition, the dose determination protocols are supported by 3D dose calculation systems

developed at several facilities in order to guarantee high safety of both therapies, FNT and

BNCT.

Manifold reasons explain the fact only a few neutron medical treatment facilities are operational

today. Some are related to technical and economic conditions, in particular ageing of facilities

followed by lengthy refurbishment programmes. Long distances from the hospitals to reactors

have made patient treatments cumbersome. Even more important, strong side effects and

statistically insufficient proof of clinical results in the early years as well as increasing

competition with new clinical methods have hindered increasing patient numbers. In fact, many

neutron facilities, and research reactors in particular, despite active participation in the R&D

stages of neutron therapy projects, actually never reached a level of patient treatment or stopped

their operation after only a few trial irradiations. Recently novel accelerator based neutron

facilities for BNCT have been developed and are currently under construction in Japan in hope of

bringing this technique inside hospitals.

2. OBJECTIVES OF THE MEETING

The Technical Meeting was expected to provide a forum to exchange good practices, lessons

learned and practical experiences in the use of neutron beam facilities for cancer therapy, both

accelerator and research reactor based. Present status, specific improvements, challenges and

future developments in neutron therapy were aimed to be addressed. The meeting concentrated

on the following major technical topics, both with relevance to FNT and BNCT:

— Description and characteristics of neutron beam facilities used for cancer therapy;

— Evaluation of the present status of neutron therapy applications;

— Recent innovations and future developments in neutron therapy;

— Biological and physical dosimetry for neutron therapy;

— Integrated treatment planning for neutron therapy;

— Accelerators versus research reactors for future neutron therapy;

— Side effects induced by neutron therapy and possible solutions for their minimization;

— Clinical and public acceptance of neutron therapy;

— Good practices and strategies for international collaboration in the field of neutron therapy.

3. WORK DONE

The meeting was attended by 30 participants representing 14 Member States and the IAEA (see

Appendix I for details). The meeting started with welcome, opening and introductory remarks by

the host organization and IAEA representatives, namely Ms G. Hampel (Johannes Gutenberg

University Mainz) and Mr D. Ridikas (IAEA), which were followed by self-introduction of all


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meeting participants. Mr F.M. Wagner (Germany), Mr A. Matsumura (Japan) and Mr R. Emery

(USA) were proposed and designated as meeting co-chairpersons.

The introductory speakers then initiated the round of presentations, beginning with IAEA

activities promoting enhanced utilization of research reactors, and later continuing with topical

sessions related BNCT and FNT as indicated in meeting agenda available in Appendix II. Short

abstracts of all presented papers can be found in Appendix III. Sufficient time was allocated for

questions-answers and follow up discussions after paper presentations as well as at the end of

each session.

The final day of the Technical Meeting was given to the collection of facilities and pertinent

characteristics for the performance of BNCT and FNT as well as discussions of the status of

research and clinical trials, areas for further R&D needed, focal points for collaboration, the

exchange of recommendations and best practices, and the advantages of utilizing accelerators

versus research reactors for neutron therapy. Furthermore, a working document has been initiated

describing the present status and recent progress, issues and challenges, action plans and

recommendations pertaining to seven aspects of neutron therapy:

1. Status of neutron therapy facilities

2. Boron and gadolinium uptake, control and time dependence

3. Clinical trial protocols and reporting of doses

4. Clinical results, including examples

5. Point of view from the medical community

6. Economic aspects

7. Public acceptance

The document was prepared and is based on inputs received from several meeting participants,

who kindly agreed to contribute on the above seven topics. These findings are presented in the

following section.

Before closure of the meeting, a technical tour to the TRIGA research reactor of Johannes

Gutenberg University Mainz was arranged. The event included a visit to the neutron beam

facilities in order to introduce its main research areas, including R&D in BNCT, and associated

neutron beam instruments.

At the very end, the participants expressed their gratitude to the host institute and to the IAEA for

organizing this meeting.


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4. SUMMARY OF THE MAIN FINDINGS

4.1 Status of neutron therapy facilities

S. Altieri, University of Pavia, Italy F.M. Wagner, Technical University of Munich, Germany

Status and recent progress

Present status of FNT facilities

At the Karmanos Cancer Center in Detroit, MI, USA, the FNT facility was closed in 2011 due to

a defect in the superconducting cyclotron. This facility was the most advanced and had recently

commissioned a delivery system for intensity modulated neutron radiotherapy. At Fermilab in

Batavia, IL, USA, the beam line at their large linear particle accelerator is to be dedicated to other

tasks; therefore medical treatments were stopped in 2013 after 36 years of operation and about

3300 treated patients. Table 1 lists the institutions able to treat patients followed by the names of

the overseeing hospitals. Only four out of six currently use their facilities.

The responsible clinician and hospital associated with each facility are:

University of Washington Medical Center: Prof G. Laramore, University of Washington

Medical Center

iThemba LABS: Prof K. Slabbert, iThemba LABS

Tomsk Polytechnic University: Prof L. Musabaeva, Cancer Research Institute, Siberian

Branch of Russian Academy of Medical Sciences

VNIITF: Prof A. Vazhenin, Chelyabinsk Regional Oncology Hospital

Essen University Hospital: Prof W. Sauerwein, Essen University Hospital

FRM II: Prof M. Molls, Klinik und Poliklinik für Strahlentherapie und Radiologische

Onkologie, Klinikum rechts der Isar, Technische Universität München (TUM)


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TABLE 1: ACTIVE FNT FACILITIES

Location

Source

reaction

(MeV)

Mean

n energy

(MeV)

50%

depth

(cm)

Beam

direction

Collimator

type

First

treatment

Patient

number Status

Treatment

planning

system

University of

Washington

Medical. Center,

Seattle, USA

Cyclotron

p(50.5)+Be 20 14 Isocentric Multi-leaf 1984 2960

Treating

patients Pinnacle

iThemba

Laboratory for

Accelerator Based

Science (LABS),

Somerste-West,

South Africa

Cyclotron

p(66)+Be 25 16 Isocentric

Multi-blade

trimmer 1988 1788

Treating

patients VIRTUOS

Tomsk Polytechnic

University, Tomsk,

Russian Federation

Cyclotron

d(13.6)+Be 6.3 6 Horizontal Inserts 1983 1500

Treating

patients MCNP

All-Russian

Scientific Research

Institute for

Technical Physics

(VNIITF),

Snezhinsk, Russian

Federation

d–t

generator 10.5 8 Horizontal Inserts 1999 1200 Standby

SERA/

PRIZM

Essen University

Hospital, Essen,

Germany

Cyclotron

d(14.4)+Be 6.5 8.0 Isocentric Inserts 1978 769 Standby Nplan

FRM II, TUM,

Garching, Germany

Uranium

converter 1.9 5.0 Horizontal Multi-leaf 2007 131

Treating

patients

Projected:

MCNPX

University of Washington Medical Center: Facility has begun its 30th

year of continuous

patient treatment in October 2013. Over the past 5 years, 62% of treatments were salivary gland

cancer cases, as compared to 25% in the first five years of operation. The facility continues to

operate well with only 0.6% of patient treatments rescheduled due to equipment failure over the

last 5 years. The biggest challenge for continued operation is dwindling patient volume, as 85%

of the facility’s operating budget comes from patient treatment. Patient volume has dropped from

142 patients in 1984 to 105 patients in 1998 and down to 41 patients in 2012.

iThemba LABS: The neutron medical treatments focus on a number of cancer types including

breast, head and neck, and salivary gland tumours. For the latter, more than 560 cases have been

very treated successfully, and a research paper has recently appeared. iThemba LABS has 25

hospital beds on site and is able to accept patients from all over the world for the administration

of fast neutrons from 9Be[p(66 MeV),n]

9B reactions as well as 200 MeV protons.


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Tomsk Polytechnic University: The 30th

anniversary of neutron medical treatment in the

Russian Federation was commemorated in October 2013. The cyclotron U120 began operation

more than 20 years earlier but still can be driven safely. Neutron irradiation applied separately

and in combination with photon therapy and surgery for treatment head and neck, salivary gland,

disseminated and recurrence breast cancer, besides a large number of publications, also a book

summarizing the clinical results until about 2010 was published in Russian.

VNIITF: The dose rate of the d–t neutron generator is very low. Nevertheless, a total dose of

only about 2.2 Gy after 8 irradiations generated significant clinical effects. The results of many

groups of patients each with reference groups and variations in adjuvant methods were

summarized in a recent monograph.

Essen University Hospital: Even though the cyclotron is in operation, the needed refurbishment

of the Essen irradiation facility has only a minimum chance to be realized. The medical know-

how in fast neutron therapy as well as in BNCT, however, is available. Therefore, suitable

patients can be irradiated at the neutron facilities of iThemba LABS and FRM II. Essen has an

agreement with the German statutory health insurance for special medical indications.

FRM II: Several physicians in southern Germany, Austria and northern Italy regularly refer

patients to the Facility for Medical Applications at Garching, MEDAPP. FNT is rather time

consuming for the physicians and physicists who have to come from the hospital in Munich to

FRM II at Garching, which is 19 km away. For patients, as the experience shows, 4–5 travels of

up to 300 km to Garching generally do not pose a great problem. The horizontal beams at FRM

II and other FNT facilities need a more flexible irradiation table or chair and more support tools

than a gantry. The task is solved by movable chairs or irradiation tables, individual masks, and

wedges or an individual vacuum sand bed. The neutron medical treatment fees that go to the

responsible hospital are generally remunerated by the health insurance of the patients. Palliative

cases of superficial tumours like recurrences of mammary carcinoma or melanoma are

predominant. Due to low patient numbers, about 25 per year, and a high variability of diagnoses,

the performance of clinical studies remained difficult.

Present status of BNCT facilities

The facilities built and employed to date for BNCT are hosted at nuclear reactors, usually in

multipurpose research centres, in which BNCT represents only a part of the activities performed.

Many of these centres have been closed due to technical or financial reasons, and therefore

BNCT activities have suffered a drastic decrease, even if the treatments were promising as in the

cases of the Boston, Petten, Řež, Studsvik and Helsinki centres. The last such a closure occurred

at the reactor FiR-1 of the VTT Technical Centre in Espoo, Finland. It was the only centre in

Europe still treating patients, and in the last few years the medical staff of Helsinki University

Central Hospital performed more than 350 BNCT treatments with very encouraging results.


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In Japan, where most clinical BNCT is being developed, the Great East Japan Earthquake of

March 2011 affected the JRR-4 research reactor located in Tokai-Mura, which has not been

restarted by the time of the meeting.

The following tables show the present status of BNCT facilities. Table 2 lists the facilities that

are being currently used for the treatment of patients followed by the names of the hospitals in

charge.

TABLE 2: BNCT FACILITIES CURRENTLY TREATING PATIENTS

Location Source Energy Flux (cm-2s-1)

Start of

medical

treatments

Patients Treatment

planning

Kyoto University

Research Reactor

Institute, Japan*

KURRI reactor

5 MW

Thermal

Epithermal

5×109

7.3×108 1989 >500 SERA

Kyoto University

Research Reactor

Institute, Japan*

Cyclotron HM30

p+Be 30 MeV–

1.0 mA

Epithermal 1.2×109 2010

Start of

clinical

trails

SERA

Tsing-Hua University,

Taiwan, China**

THOR TRIGA

reactor,

2.0 MW

Thermal

Epithermal

1.34×108

1.07×109 2010 >17 THORplan

*Responsible hospital: Osaka Medical College, Osaka; **Responsible hospital: Taipei Veterans General Hospital, Taipei

Table 3 lists the facilities that have been planned to start treatments in the near future and Table 4

includes those projected to begin. With an appropriate beam shaping assembly a thermal or

epithermal beam will be realized. For these facilities, the design of the neutron source, a proton or

deuteron accelerator, is ready, and some of their parts have been already constructed.

TABLE 3: FACILITIES WHERE BNCT PATIENT TREATMENT IS PLANNED IN THE NEAR FUTURE

Location Neutron source Energy Project status

High Energy Accelerator

Research Organization

(KEK), Japan

Radiofrequency quadropole linac (RFQ)

p+Be

8 MeV–10 mA

Epithermal Start in 2014–2015

CNEA, Bariloche,

Argentina

RA-6 reactor

2 MW Hyperthermal Restart in 2014


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TABLE 4: FACILITIES THAT ARE PROJECTED TO BEGIN TREATMENT OF PATIENTS

Location Neutron source Project status

National Cancer Center

Hospital, Japan

RFQ p+Li

2.5 MeV–20 mA Under construction

Birmingham University,

UK

Dynamitron p+Li solid

2.8 MV–1 mA Upgrade to 4 mA

Legnaro National

Laboratories, Italy

RFQ p+Be

5 MeV–30 mA

Under construction

Project to be installed in Pavia

Tandar Laboratory,

Argentina

Tandem electrostatic quadropole accelerator

Be(d,p)Li solid

5 MeV–30 mA

Under construction

Soreq Nuclear Research

Centre, Israel

RFQ p+Li liquid

4 MeV–1 mA Under construction

Moscow Engineering

Physics Institute,

Russian Federation

RR, 2.5 MW Animal experiments

Budker Institute of

Nuclear Physics, Russian

Federation

Vacuum insulated tandem accelerator 7Li(p,n) solid

2 MeV–2 mA

Under construction

Institute for Physics and

Power Engeineering,

Russian Federation

Cascade generator

KG-2.5

2.3 MeV–3 mA

Under construction

China Institute of

Atomic Energy, China

In-hospital neutron irradiator

(30 kW research reactor) Biological experiments

Institute of Atomic

Energy POLATOM,

Swierk, Poland

Maria RR, 30MW

R&D, treatment planning development,

pre-clinical trials

Below text briefly describes some considerations related to the neutron beam intensity, quality,

advantage depth and ratio, divergence, and beam purity.

Beam intensity

The dose absorbed in a tumour due to the reaction 10

B(n,α)7Li depends on the thermal neutron

fluence and the concentration of 10

B in the tumour during the irradiation; thus the irradiation time

also depends on these factors. To date, an attainable value of boron concentration in a tumour is

approximately 30 ppm. With this value, the thermal neutron fluence considered sufficient is of

the order of 1013

cm-2

. To achieve this fluence, the irradiation time depends on the available beam

intensity. The currently used neutron beams have intensities of the order of 109 cm

–2s

–1 which

correspond to an irradiation time of 50–60 minutes for each field.


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The minimum beam intensity required must ensure that the treatment time is compatible with a

comfortable and secure patient irradiation and that the boron concentration in the tumour, normal

tissues and blood does not vary greatly during the treatment itself.

Beam quality

Neutron energy is a fundamental characteristic of the beam quality. For the irradiation of shallow

tumours thermal neutrons (<0.5 eV) are suitable, while for deeper malignancies epithermal

neutrons in the range 0.5 eV–10 keV must be employed. When using thermal neutron beams, the

intensity can be equal to the neutron flux at the entrance of the tumour, while in the case of

epithermal neutrons, the maximum thermal neutron flux is produced at about 2 cm in tissue. In

this case, the maximum value of the thermal flux can be assumed as equal to the epithermal flux

at the surface. At farther depths inside tissue, the thermal neutron flux decreases to about 50% of

the maximum at around 6 cm. This means that for deep tumours irradiation time is twice as long

as those for shallower tumours.

Beam advantage depth (AD) and advantage ratio (AR)

To measure the penetration of particular neutron beams, two considered in-phantom figures of

merit are the parameters AD and AR. AD is defined as the depth in the phantom at which the

dose absorbed by the tumour is equal to the maximum dose delivered to healthy tissue. AR at a

particular depth is defined as the ratio between the dose absorbed by the tumour and the

maximum dose absorbed by healthy tissue.

The AD of the existing BNCT beams ranges between 8 and 10 cm. Filters of pure 6Li 8–10 mm

thick harden the neutron energy spectrum and provide a significant increase in AD, thereby

improving dose coverage for the deepest tumours. The AR varies between 5 and 6 in most beams

when using the delivery agent Boronophenylalanine (BPA).

Beam divergence

A collimated neutron beam guarantees a higher penetration, a thermal neutron flux more uniform

in the whole tumour thickness and the easiest patient positioning. In fact, a low divergence makes

the intensity of the beam decrease slowly with the distance from the collimator; thus it is not

necessary that the patient is positioned in contact with the collimator. A parameter that is often

considered is the ratio between the neutron current and the neutron flux. The recommended value

for this ratio is 0.7.

Beam purity

For the irradiation of deep tumours, epithermal neutrons are used to spare the tissue surrounding

the tumour; thus it is important to reduce the thermal contamination that could determine an

unwanted dose. The recommended ratio between the thermal and epithermal flux is equal to 0.05.


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BNCT selectivity depends on the boron concentration ratio between tumour and normal cells, and

the dose is delivered selectively through the reaction 10

B(n,α)7Li induced by thermal neutrons.

All other types of radiation, in particular fast neutrons and photons, tend to decrease the

selectivity of the treatment. For this reason these unwanted components must be minimized as

much as possible. As a reference, for each component is considered the dose per unit of beam

fluence. This dose of both fast neutron and photons must be kept below 2×10–13

Gy·cm2. The

dose values achieved in the beams currently operating range between 1.4–17×10–13

Gy·cm2

for

fast neutrons and between 1–11×10–13

Gy·cm2 for photons.

The transition from the neutron source achieved by a reactor fission spectrum to one obtained

with an accelerator offers the possibility to install the neutron source inside a hospital as well as a

contribution to the improvement of the neutron beam quality. This is especially true if the energy

of the protons used to produce neutrons can be maintained low, thus decreasing the fast neutron

contamination. To this end, the reaction 7Li(p,n)

7Be seems to be more advantageous, even if it

produces 7Be, which in turn contributes to the gamma background. Furthermore, the spectrum of

neutrons produced with accelerators can be modelled with proper beam shaping assemblies in a

way that a peak at a value of some keV occurs, differing from the spectra at reactors, which peak

at energies of some eV. This increases the penetration of the beam by about 2 cm as compared

with existing spectra.

Another effort attempts to increase the beam intensity in order to treat patients in times of some

minutes. The fulfilment of this goal can be supported by the development of new boron carriers

more selective for a given tumour and able to ensure boron concentrations about five times higher

than the formulations presently employed. Moreover, the development of a liquid lithium target

at Soreq Nuclear Research Centre, Israel, may solve the cooling problem and allow for higher

neutron fluxes, while at the same time meeting the required beam quality.

Recent developments

Developments in FNT

University of Washington Medical Center: Nearly completed accelerator and therapy control

system upgrades include a digital imaging and communication in medicine (DICOM) server to

interface with the treatment planning system and potentially an oncology information system.

Pinnacle treatment planning system for fast neutron planning has been commissioned. MCNPX

model is to be used for plan verification with the eventual goal of using it as a treatment planning

engine. The imaging system has been upgraded. Future plans include upgrades to dosimetry and

multi-leaf collimator controllers to provide potential for intensity modulated treatments.

Tomsk Polytechnic University: in progress, clinical studies of FNT on stem cells in different

tumours resistant to low density ionizing radiation; planned, development of new dose planning

system and mathematical models to predict response of resistant tumours as a function of

delivered dose.


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FRM II: A new multi-leaf collimator with sharper margins is under construction as well as the in-

house development of a dose planning system. Palliative cases are now more predominant than in

the 1990s. Due to low patient numbers and variability of diagnoses, clinical studies are not

planned.

Developments in BNCT

After many years of research and development, the first centres for BNCT treatment with neutron

sources obtained with proton accelerators are beginning operation. The first is the cyclotron at the

Kyoto University Research Reactor Institute, Japan, followed by the RFQ at KEK, Japan, which

is planned to begin patient treatment in 2015. Other projects could be ready in the next few years.

These new facilities will potentially replace the ones based on nuclear reactors and can be

installed directly inside hospitals.

General issues and challenges

Medical use of neutron sources often was introduced at established physics institutes. This

approach needs an especially high and continuous level of cooperation from the side of the lead

clinicians. Longer and not always regular maintenance periods of reactors, including their remote

location from hospitals, however, have limited the acceptance of neutron therapy by clinicians.

Backup capacities with a clinically similar beam quality are normally not within reach. New

developments like IMRT as well as the misgivings concerning late effects of FNT, are the

reasons why FNT suffers from a lack of interest among clinicians, which in turn, causes FNT

facilities to treat fewer patients and to suffer from underutilization or to be shut down altogether.

Without renewed interest in the form of research and clinical trials, FNT will cease to exist.

Additionally, clinicians who originally championed FNT are near the age of retirement, instilling

much uncertainty in the future of FNT. The best chance for continued FNT is with established

clinicians at existing facilities. Promotion of FNT beyond this will be very difficult.

For the future of BNCT, a critical requisite for the administration of BNCT to patients in a stable

and long term programme is the possibility to create centres of purpose to design both the neutron

beams and other medical facilities needed. These structures must be integrated in hospitals, and

the neutron source must be completely independent from other experiments, similar to hadron

therapy centres, and configured as small hospitals dedicated to this application.

Technically it is possible to employ a small nuclear research reactor as a neutron source totally

dedicated to BNCT from the beginning of its use. Nuclear reactors, however, are not generally

accepted in a hospital environment, and for this reason there has been a significant effort by the

scientific community to design and construct neutron sources with intensities, ~1013

–1014

cm-2

s-1

,

and energy ranges of a few keV, suitable to obtain thermal–epithermal collimated neutron beams

with fluxes of at least 109 cm

-2s

-1 using charged particle accelerators.


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Clinical studies in both FNT and BNCT are difficult due to small patient numbers, even though

they are currently indispensable. Nevertheless, all available patient data should at least be

collected and evaluated with help of suitable data banks and associated analysis methodologies.

At Tomsk Polytechnic University as well as at the Russian Academy of Medical Sciences,

monographs have been published containing evaluated data from nearly 200 of patients (see

bibliography). Unfortunately, their print runs were so low that these editions were exhausted

before they became known in other countries. The challenge is to disseminate this knowledge

outside the Russian Federation.

Conclusions and Recommendations

Recommendations to the community

Extending the follow up with patients as long as possible and the standardization of data banks is

most vital. As latent effects have damaged the reputation of neutron therapy in the past, long term

observation of patients must be performed by hospitals that have left the community. The results

can also help to make BNCT safer, as similar side effects may be generated by contaminating fast

neutrons. Try to meet the usual local clinical requirements also at older and non-hospital based

facilities. The important conference series Young Researchers BNCT Meetings should integrate

FNT, because the two fields have common interests, e.g. the quantification of biological effects,

appropriate integration of results in dose planning and interpretation of side effects, among

others.

Recommendations to the IAEA

Initialize translations of the Russian books on FNT published by Tomsk Polytechnic University

and VNIITF. Electronic versions could be hosted at the neutron therapy homepage. Support the

standardizing of the structure of patient data banks in order to facilitate the dissemination of

experience. Within the possibilities of IAEA, encourage better standardization of dosimetry in

BNCT.

4.2 Boron and gadolinium uptake, control and time dependence

A. Lipengolts, Moscow Engineering Physics Institute, Russian Federation


Neutron Capture Therapy (NCT) is a binary technology utilizing two independent factors, a

neutron beam and boron or gadolinium in the form of a pharmaceutical, whose interaction results

in unique local radiation to provide a huge therapeutic effect on a tumour. The amount of boron

or gadolinium to a great extent determines the efficacy of NCT performance. For example the


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value of a so called boron dose can comprise from 50–80% of the total absorbed dose during

BNCT irradiation. Thus underestimation of boron content in healthy tissue can lead to a great

damage as well as overestimation of the boron concentration in tumour tissue can cause a lack of

radiation exposure (at the tumour).

Boron and Gadolinium Carriers

Boron and gadolinium are suitable as beam-targeting radiation therapy (RT) enhancer elements

for neutron therapy. Both have for therapy to be included in a molecular form, which is

biocompatible (no toxic, no late side effects) and has an elimination pathway. Suitable molecular

forms are for Boron BPA and BSH and derivatives of those, for Gadolinium complexes with

DTPA and derivatives. Both enhancers need an uptake into the cancer cells (<10 µm distance to

the DNA), Gadolinium needs to close or inside to the cell nucleus. The efficacy as RT enhancer

is a product of the local concentration inside the cancer cells, the physical cross section at the

local neutron energy (E(x)), and the local energy deposition rate of the produced energy, i.e. in

a 1 cm volume around the therapy target centre.

The therapy materials were improved by biological targeting to the cancer cells by addressing

their receptor-ligand recognition systems with drug carriers in two concepts: (a) in molecular

carriers (Ross, Altieri) the receptor ligand is directly loaded with limited number (1-4) of

enhancer complexes, e.g. BSH; (b) in nanoparticles based attempts (liposomes, polymers,

bioinorganic particles; Wittig, Nawroth, Japanese groups), a large number of enhancer molecules

(millions) is located in particles of 100 nm size, which are linked to the receptor ligands. Both are

taken up by the cells by endocytosis. Thus the cellular concentration shows a time profile after an

administration.

Boron Control and Time Dependence

The task of boron quantification in clinical practice can be divided into two major tasks:

obtaining information of boron content for treatment planning and the determination of actual

absorbed dose after neutron irradiation. The current approach to boron in vivo quantification is

based mostly on measuring boron concentration in blood and using a tumour-to-blood ratio

(TBR) to determine the boron concentration in the tumour. TBR is usually determined as an

average from experiments with animals and special separate studies of humans. This method

answers the purpose of treatment planning by measuring the boron concentration after drug

administration. For dosimetry purposes the results of additional measurements of boron

concentration in blood are also used as well as some pharmacokinetic models to estimate boron

concentration change during irradiation. The average TBR approach is not universal and cannot

provide reliable information for treatment planning and dosimetry.


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For obtaining information on boron or gadolinium distribution before irradiation for treatment

planning, modern medical visualizing methods such as magnetic resonance imaging (MRI),

single photon emission computed tomography (SPECT) or positron emission tomography (PET)

can be used.

The results of TBR measuring by Japanese scientists using PET show that even for the same type

of tumour, e.g. squamous cell carcinoma, the TBR value can vary from 2.1 to 8.0 from patient to

patient (J. Itami, Mainz, 2013) as well as the rates of accumulation and elimination. One should

also mention that the TBR approach assumes a uniform boron concentration in the tumour, which

is inaccurate. To improve the existing TBR approach Japanese scientists conducted a PET study

with 18

F-BPA prior BNCT irradiation. This method significantly improved treatment planning,

but the amount of the drug administered during the PET study and during BNCT procedures

differ by several orders, and the actual bio-distribution and pharmacokinetics can differ from the

data obtained in PET studies.

Utilization of specific radiopharmaceuticals makes the BNCT procedure even more complex and

demands additional permissions for application from authorities. Finally, not every compound

can be easily labelled with 18

F or another positron emitting nuclide, e.g. using 18

F is still not

possible for sodium borocaptate. NCT, therefore, requires a tool for in vivo quantitative imaging

of 10

B and 157

Gd for proper treatment planning and dosimetry.

MRI seems to be the most suitable technique for boron and gadolinium visualization and

quantification. Physical properties of 10

B and 157

Gd are highly conducive for MRI for these

purposes. Gadolinium can be easily visualized with good space resolution even on existing

medical MRI scanners, but for quantification aims new reconstructing algorithms should be

developed. In the case of 10

B modification a MRI scanner is necessary as well as data acquisition

and image reconstructing algorithms. Nuclear magnetic resonance detection of 10

B is a rather

challenging technical task, and at the moment the possibility for visualization and quantification

of 10

B directly with satisfactory space resolution by MRI is unclear. Another way to use MRI in

BNCT is using a marker, e.g. Gd or 19

F, for labelling a BNCT drug using the same approach as in

PET but without the radioactive marker.

For dosimetry aims in NCT one potentially powerful tool is prompt gamma single photon

emission tomography (PG-SPECT). This process is based on detection of prompt gamma

radiation emission by isotopes under study, e.g. 10

B, 157

Gd and 1H, with a ring of detectors and

the subsequent reconstruction of the neutron capture events distribution on a particular element.

This information allows the visualization of the actual boron or gadolinium dose and thermal

neutron distribution in the patient. The most challenging task in implementing PG-SPECT is the

detection system. The detection system for PG-SPECT should match several, in some degree

conflicting, demands: good energy resolution for separating certain prompt gamma lines, high

detection efficiency and tolerance to neutron damage. Preliminary simulations performed by

Japanese and Argentinean scientists have shown the possibility of PG-SPECT with a space


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15

resolution of 10 mm and a detecting limit of 10 ppm for 10

B, but these have not been proven

experimentally yet. For example, a prototype PG-SPECT is planned to be build up at MARIA

reactor, Poland, and tested to detect newly developed boron carriers and pharmaceuticals.


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16

Issues and Challenges

The local enhancer concentration in the tumour cells and enrichment factor, as compared to

healthy tissue, at the irradiation time needs and can be improved (TBR > 5-10). A further gain

and reduction by one magnitude is possible by further improvement of the enhancer delivery and

treatment plan.

Summarizing the methods of boron quantification in clinical practice, there is still a need to

enhance detection limit, spatial resolution and verifying these methods in-vivo, to obtain

treatment planning and dosimetry.

Conclusions and recommendations

According to the development of porphyrins as boron carrier, one must find a way for their

reproducible industrial synthesis. Nanoparticles designed to increase the damaging agents uptake

(B/Gd) in cells, should be functionalized with targeting agent (e.g. folic acid, amino acid,

peptide) and a visualizing marker. Therefore, tight interaction of projects focused on B/Gd

analysis and nano-carrier development is required. This has to combined with a treatment-case

list of cancer types, where (B)NCT offers best opportunities, as compared to other RT types

(hadrons, ions, photons). The future development and acceptance of BNCT as conventional

medical treatment modality depends to a high degree on developing tools for in vivo boron and

gadolinium distribution control.


o Build up network with direct project interaction

o Share the experience potential, already studied boron drugs

o Conduct an experiment to determine the properties and possibilities of PG-SPECT

techniques conducted with collaboration among the leading institutions in this field

o (If necessary) Develop and upgrade for visualizing scanners for measuring a marker in the

NCT drug

o Conventional diagnostic methods such as MRI, PET and SPECT can be adopted for

purposes of boron and gadolinium control in NCT.


o Support networking with direct project interaction, e.g. web portal

o Inspire tomography scanner manufacture to develop special experimental tools for boron

and gadolinium visualization and quantification for NCT clinical trials. The MRI method

is preferable.


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4.3 Clinical trial protocols and reporting of doses

W. Sauerwein, University Hospital Essen, Germany


Well-designed clinical trials are essential for medical progress. Any new treatment modality must

be proven first to be safe, second to be efficient, and third to be superior to established therapies

before eventually become accepted as a new standard. To ensure protection of research subjects,

the conduction of clinical trials is strictly regulated by national laws based on international

guidelines. A clear design for clinical trials to test implement binary treatment modalities such as

BNCT is still missing.

Issues and challenges

BNCT clinical trials

The treatment concept of BNCT varies fundamentally from conventional therapies. The main

distinctions are the binary nature of the treatment principle, which requires investigation of an

effective compound for targeting and eradicating tumour cells without its own therapeutic effect.

Radiation facilities and beams used for BNCT to date differ considerably not only from facilities

and beams used for conventional radiotherapy, but also among themselves. In addition they often

must first be licensed for patient treatments. Therefore, the development of BNCT to treatment

modality needs strategies that are based on the classical trial concept but meet the challenges and

characteristics of the process. Understandably, all applicable laws and regulations for conducting

clinical trials must be respected. These aspects make clinical trials in BNCT a challenging task

for clinical scientists as well as regulatory authorities.

To this point, pharmaceutical companies have exhibited no interest because of a lack of a market.

BNCT has been historically extremely expensive without support from public funding.

Candidate tumours for FNT

Hypothetical candidates include:

Tumours with high capacity to repair radiation damage by photons surrounded by healthy

tissues with a low capacity to repair such damage;

Tumours with a high amount of hypoxic areas;

Tumours with diffuse infiltration of healthy surrounding tissues.

A tumour with well delimited margins is suitable for other radio-therapeutic modalities based on

steep dose gradients at the field edges.


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Conclusions and Recommendations

No BNCT treatments should be conducted outside trial protocols, which can be developed by

BNCT community members but should be approved only after reviews by international review

committees in which non-BNCT clinical scientists also participate.

If possible, organize clinical trials in the frame of established structures such as the European

Organisation for Research and Treatment of Cancer and the US National Cancer Institute.

Make ongoing protocols visible by registering BNCT clinical trials at the US National Institutes

of Health online database at www.clinicaltrials.gov, in which 13 BNCT trials are already

registered, and in national databases.

Allow patient recruitment from outside (include colleagues from academic hospitals that do not

have a BNCT facility as investigators in the trial to perform the follow up). The switch from

reactor based neutron sources towards accelerator based neutron sources that can be installed in

hospitals must be reported as much as possible. The pharmaceutical industry must realize a

potential market. If such accelerator facilities will be available in 10 years, drug development

must begin now.

To avoid misunderstanding and the impression of a lack of seriousness, only clinical scientists

should present clinical trials and medical aspects of BNCT to the medical community and public.

A consultancy meeting tentatively titled Prescribing, Recording and Reporting Doses in BNCT is

recommended.

The International Society for Neutron Capture Therapy should create a database to collect data

and conclusions from ongoing and completed clinical trials. In review of the organization’s

structure, the role of president should be separated from the role of organizer of the biennial

congress for better representation of the BNCT field by an established and recognized scientist.

In this regard, the International Society should consider creating a real membership. These

members should promote BNCT in the frame of their own national and international scientific

societies.


Inside the IAEA, aid to BNCT research efforts should become a topic during programme

planning. Contact could be established between the IAEA Division of Human Health and

clinicians involved in BNCT. A successor to IAEA TECDOC 992 “Nuclear Data for Neutron

Therapy: Status and Future Needs” should reflect advances in research and would be highly

beneficial. The IAEA could be a useful medium to facilitate cooperation between BNCT

clinicians and the International Committee on Radiation Units and Measurements.

http://www.clinicaltrials.gov/


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4.4 Clinical results of BNCT and FNT

A. Matsumura, University of Tsukuba, Japan

A. Wittig, Philipp University of Marburg, Germany

Present status and recent progress

Present status of BNCT trials

Several small case control studies using research reactors have concluded with favourable

outcomes for such tumours as glioblastoma, malignant melanoma as well as head and neck

cancer. The usage of the reactor has restrictions stemming from the number of the patients treated

by BNCT and also the variety of the cancer types that may be considered for possible application

of BNCT.

18F-BPA PET was used for the selection of patients as candidates for BNCT. If the

18F-BPA

shows relatively high accumulation, the treatment effect of BNCT could be anticipated so that a

kind of personalized medicine could be applied. Secondly, the boron concentration of the tumour

and normal brain tissue could be estimated from the PET image so that a rough estimation of the

given irradiation dose could be made. However, since the PET image resolution is only at mm

level, high accuracy cannot be expected. The boron concentration in individual cells could not be

measured due to the heterogeneity of the boron accumulation based on the cell cycles, blood

supply and other microscopic environment. It must be mentioned that this is not specific to

BNCT but also in anticancer agent treatments in the usual clinical settings. We applied the

chemotherapeutic agents without knowing the concentration at microscopic level. The same

uncertainty in chemotherapeutic agent distribution as mentioned above persisted, but we looked

at the overall tumour response in the clinical settings.

In BNCT, the dose prescription is based on the normal tissue tolerance dose, which has been

described from past clinical studies, and we also could estimate roughly the tumour dose from the

PET scan, which resulted in higher doses as compared to conventional radiotherapy. Hence, the

clinical results of BNCT for glioblastoma showed a better median survival time, 11.2 months for

conventional radiotherapy versus 25.6 months for BNCT, in the clinical case control study. This

should be further investigated with larger case control studies.

In the future, if accelerator based BNCT become feasible, a randomized control study might be

possible within a multi-institutional clinical study. Whether to perform a randomized control

study is still in debate since it has been proven that if one can give higher dose to the tumour

without normal tissue damage, the clinical results are superior to cases of lower radiation doses.

Hence, the critical issue is to give higher doses to the tumour without having normal tissue

damage in the early as well as late stage. Clinical studies in BNCT based on this concept should

be performed.


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Several treatment planning systems for BNCT such as SERA, MacNCT and JCDS have been

developed. The treatment planning system is essential for the planning of the treatment as well as

for post-BNCT evaluation. Treatment planning is implemented simultaneously with the patient

setting system, and the accuracy of such coordinating systems should be further improved and

simplified to be tolerated for broader usage in in-hospital accelerator BNCT.

Present status of FNT trials

Since 1985, researchers in Munich using the FRM I and FRM II reactors have irradiated

approximately 850 patients, 90 % under palliative intent. Using an unmoderated highly enriched

uranium fuelled fast to thermal neutron converter and a multi-leaf collimator with a maximum

opening of 30×20 cm2 (width by height), candidate tumours are irradiated with a spectrum of

mean energy 1.9 MeV neutrons and 2.4 MeV photons. A neutron flux of 3.2 × 108 cm

-2s

-1 has

been achieved, and neutron beams are typically administered in 4–6 fractions subsequent to a

photon or electron treatment.

The most frequent indications have been lymph node or skin metastases from cancers of various

origins, predominantly chest wall metastases of breast cancer, for which FNT is advantageous

due to the low penetration length of the beam and consequent low dose to the heart and lungs.

Curative indications at this facility include adenoid cystic carcinoma of major salivary glands in

an adjuvant setting; recurrent malignant melanomas and soft tissue tumours in certain locations

and local relapse of breast cancer occurring after conventional irradiation in women with no

distant metastases.

Additionally, iThemba Labs facility hosts a 200 MeV cyclotron to produce high energy neutrons

for treatment of approximately 1800 patients from 1989–2013. The range of tumours includes

unresectable tumours and those for which surgery is considered suboptimal as well as

macroscopic residual disease after surgery. Neutrons are produced from a reaction of high energy

protons on a beryllium target for a beam with negligible photon contribution similar to 8 MV X

ray. Treatment is arranged via a locally developed pencil beam method and VIRTUOS software.

FNT has shown particular success in the treatment of salivary gland tumours according to a

recent study by Stannard et al.


Feedback from new basic research to clinical trials

Vigorous basic research on developing accelerator neutron sources and new boronated drugs has

been performed. These activities should be quickly applied to clinical research. There has been so

far high interest at the academic level but lower interest at the socioeconomic level because the

neutron source was limited to research reactors and BNCT could not be applied as a usual

medical treatment, being rather regarded as an experimental therapy. However, the development

of accelerator based neutron sources may enable BNCT within hospitals so that the number of the


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patients may increase dramatically. In this case, development of new boronated drugs may attract

the pharmaceutical companies.

Cooperation for the performance of a large volume clinical trial

Since BNCT is performed in an extremely limited number of places, it is urgent that one clinical

protocol should be performed with multiple institutions to show the efficacy of BNCT by means

of the statistical evaluation of a number of patients. Such a study is, however, difficult because

the beam shape differs from facility to facility. Nevertheless, the creation of a strong clinical trial

team like the Radiation Therapy Oncology Group and Japan Clinical Oncology Group is vital to

convince physicians and patients.

Recruitment of medical doctors for interest in BNCT

Since BNCT is a very complicated therapy using boronated drugs and neutrons, education and

promotion of BNCT is essential to attract medical doctors, who are not familiar with BNCT.

Providing stable and convenient neutron sources for clinical trials and treatment

Research reactors can provide an ideal neutron beam for BNCT, such as epithermal neutrons with

relatively low high energy neutrons. However, nuclear reactors have several disadvantages. One

is locations generally far from hospitals, which is inconvenient for patients and the medical team.

Treatment facilities located within hospitals would be much easier, safer and convenient.

Accelerator based neutron sources may solve this problem in the future.


Selection of appropriate tumours for BNCT

BNCT could be applied to newly diagnosed, invasive types of cancers such as glioblastoma,

multiple tumours and already irradiated cancers that are not a qualified candidate for other

radiation therapeutic modalities. Radiation resistant cancers are also good candidates for BNCT

since alpha particles are charged particles with high linear energy transfer. To summarize trials of

various tumours, the types that have generally responded well to BNCT include:

Well-differentiated salivary gland tumours;

Soft tissue, chondro- and osteo-sarcoma;

Locally advanced prostate cancer (due to progress in conventional radiotherapy this has

become a questionable candidate).

Questionable results have been achieved for:

Locally advanced head and neck cancer;


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Medullary thyroid cancer;

Locally recurrent breast cancer after radiotherapy;

Renal cell cancer;

Recurrent carcinoma of the rectum;

Large masses of malignant melanoma;

T4 cancer of the uterine cervix and of the bladder.

Those that have achieved poor results in clinical trials include:

Glioblastoma;

Esophageal cancer;

Stomach cancer;

Pancreatic cancer;

Lung cancer.

Indications for BNCT

Since 18

F-BPA PET may show the accumulation of the applied drugs in each cancer type,

screening with 18

F-BPA PET may result in new indications for BNCT. If the labelling of specific

molecular targeting agents with radioisotopes becomes feasible, one may find new indications for

BNCT in the future.

Approval of medical equipment and boron drugs

In Japan, the first clinical trial of accelerator based BNCT has applied for approval of medical

equipment and medical drugs from the Japanese Pharmaceutical and Medical Devices Agency.

After approval of the medical equipment and drugs, qualification for health insurance coverage is

the next step to broaden the number of the BNCT treated patients. Since health systems vary

from state to state, individual efforts are warranted in each.

The treatment cost for BNCT should be ideally acceptable to patients as well as to health

insurance companies or public health services.

Actions for consideration by the BNCT community

Through efforts to treat various types and stages (newly diagnosed or recurring), the BNCT

society must demonstrate the therapeutic efficacy to the medical community and public prior to

acceptance as a radiotherapy modality.

For newly diagnosed tumours, a case control study (Phase I/II) to prove safety, a large volume

case control study to prove efficacy and a randomized control study may be considered.


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Actions for consideration by the IAEA

BNCT has yielded complex issues such as the use of 18

F-BPA PET for evaluation of boron

accumulation and selection of proper candidates, treatment planning systems with patient setting

systems and accelerator based neutron sources for in-hospital based BNCT. The IAEA, therefore,

could guide society and relevant personnel to the proper and effective usage of BNCT treatment

modalities with optimized standards. For this purpose, revision of IAEA-TECDOC-1223 is

crucial since the last version was published in 2001 without a description of the clinical results or

a significant description of the usage of accelerator neutron sources.

4.5 Point of view by the medical community

B. Al-Nawas, University of Mainz, Germany

H.M. Specht, Technical University Munich, Germany

Status and recent progress in Cancer Therapy

The methods of treating cancer which are well admitted in the medical community are resection

by surgery, chemotherapy, photon therapy and molecular target therapy. It is to mention that

there is no single “best” therapy hence cancer is always treated by multimode therapy. The

question then which is raised regarding future of the BNCT, after the closing of treatment centre

in Finland: “should we just let a technique die?”

Clinical studies using BNCT have mostly taken place in palliative treatment and given only few

accepted indications yet. There are no studies available with a high level of evidence. This leads

still to the challenge of increasing the knowledge of tolerable doses and treatment schedules.

Currently used indications are:

Glioblastoma

Adenoid Cystic Carcinoma

Oral Squamous Cell Carcinoma

Skin Cancer

Thyroid Cancer

Breast Cancer.

As it is illustrated in Fig. 1, clinical investigation using BNCT in treating head and neck cancer

gives an indication of success.


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FIG 1 Locoregional failure-free survival after BNCT: The patients censored are indicated with a

bar. Two- and four-year survival figures are provided. CI = confidence interval.

Issues and Challenges

The biggest issues and challenges in the medical point of view can be summarized in four points:

1. No ongoing trials in FNT, only single institution trials in BNCT

2. Rapid development in photon treatment, keen competition

3. Only few institutions worldwide will make new studies difficult

4. No agreement on study protocols


Any clinical trial needs a homogeneous, large numbered group of test persons. Based on such

requirements, it makes sense to strengthen worldwide cooperation and make joint publication of

achieved treatment results. Particularly, it is applicable to the new accelerator-based BNCT

centres.

There is also a need to design studies focusing on QoL for palliative indication. Thinkable

candidates are breast cancer recurrence and malignant melanoma.

By addressing organ specific specialists, e.g. in head and neck treatment, BNCT will create

awareness for therapy.


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Create consensus conference on BNCT with medical and technical experts

Joint publications of achieved treatment results (homogeneous groups with large number,

e.g. ACC)

Prove the usefulness of neutron therapy in palliative treatment indications (growing

importance of palliative treatment with improving cancer therapy)


Assist in organizing consensus conferences/workshops

Assist in formulating single arm study protocol for 3 -5 entities

Overview over the centres activities

Identify centres which need support in establishing contacts with physicians.

4.6 Economic aspects

Jun Itami, National Cancer Center Hospital, Japan


With the progress of accelerator and target material technologies, the high flux of epithermal

neutrons required for BNCT can now be obtained through accelerator and target systems. The

assumptions for an analysis of the economic aspects of accelerator based BNCT are as follows:

BNCT accelerator cost: US $26 042 000;

Facility building: US $6 250 000;

Yearly electricity: US $156 250;

Yearly salaries:

o 3 medical doctors: US $417 000;

o 1 pharmacist: US $78 200;

o 2 medical physicists: US $167 000;

o 3 radiation therapy technologists: US $187 500;

o 2 nurses: US $115 000;

BPA cost per patient: US $5 250;

6 years for depreciation.

As shown in the graph Fig. 2, the cost per patient decreases very rapidly from US $57 274 for 0.5

patients treated in one day to US $8501 in the case of 8 patients treated in one day. Although

absolute costs differ according to the amount of initial investment, the cost per patient always


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follows rapidly decreasing curve.

For comparison, typical costs for the treatment of patients at research reactor facilities are of the

order of US $ 40,000 per patient.

FIG.2. Chart of BNCT cost in US$ per patient treated in one day: presented as a function of

number of patients treated.


Beyond modelling and analysis, to establish BNCT as a cost efficient therapeutic modality,

demonstrating evidence of the clinical significance of BNCT and persuading medical society are

imperative. Modern medicine demands properly performed clinical trials. To perform such

clinical trials, to establish the clinical significance of BNCT, hospital based BNCT systems are

mandatory. With hospital based systems patient recruiting and management will be quite easy.

Unfortunately, there have not been sufficiently good quality clinical trials of BNCT yet. If a

significant clinical benefit of BNCT is demonstrated, more enthusiasm will emerge for the use of

existing research reactors for BNCT.

Another approach to extend the application of BNCT is the development of new boron carriers

that can selectively accumulate in cancer cells.

0

10000

20000

30000

40000

50000

60000

70000

0 2 4 6 8 10

BNCT cost ratio


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The development of hospital based accelerator BNCT systems and the performance of properly

organized clinical trials of BNCT are mandatory to show the clinically significant benefit of

BNCT to medical, particularly oncological, societies.

The development of new boron carrier compounds that selectively accumulate in cancer cells

should be further explored.

Accelerator systems used in BNCT are quite new area for this technology. The IAEA is an ideal

third party to propose the minimal technological requirements and standardize radiation safety

recommendations for accelerator based BNCT. Because BNCT is a binary procedure employing

neutrons and drugs, the acquisition of official regulatory permission for accelerator based BNCT

is very complicated and demanding. Regulatory agencies must judge the neutron emitting device

and boron compound simultaneously. If an international third party like the IAEA proposes

minimal requirements and prerequisites at least for the neutron producing device, this would

facilitate decisions by national regulatory agencies.

4.7 Public acceptance

D. J. Grocott, The Cyclotron Trust, United Kingdom

Present status and recent progress

Neither BNCT nor FNT have any public acceptance or profile. Developments in Japan for BNCT

and, most significantly, the central Tokyo hospital based BNCT facility now under construction

deserve of international publicity.


Direct public campaigns for either BNCT or FNT would be expensive and difficult. Individual

advocates and advocacy groups who will communicate the benefits of these treatments are

required, rather than waiting for the informal spread of information within the medical

community. In addition, the word neutron in a medical context has a negative connotation and

could contaminate any publicity for BNCT or FNT. This is a challenge in attempts to build a

single community of BNCT and FNT clinicians and researchers.


The Technical Meeting participants agreed to set up a discussion forum. This should be used

constantly to remind the community of the need to publish results and to press release to

professional and lay media regarding successes in therapy. These releases can only come from


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institutions, not from the community. A public awareness champion to goad institutional action

must be appointed.

All who practise in the field of neutron therapy should demonstrate that theirs is good medicine.

Individuals cannot leave the publicity that will change perceptions to others. Everyone must be a

leader in promoting the role of neutrons in medicine. The IAEA could, by supporting BNCT,

bring a single event method to cancer treatment across the globe. The IAEA could, by supporting

FNT, keep a small but valuable treatment option alive. Without the IAEA's leadership FNT will

be a regrettable casualty of competitive medicine.

5. EXECUTIVE SUMMARY

The Technical Meeting was highlighted as a successful and useful event by the meeting

participants, representing both research reactor and accelerator based facilities involved in two

varieties of neutron therapy for the 1st time, namely FNT and BNCT. The support for the meeting

in terms of the number and diversity of participants as well as participating Member States is a

significant indicator of the success of the broader endeavour — to provide timely practical

assistance and support the sharing of research reactor and accelerator based neutron source

experience related to the provision of nuclear data, foster the development of new experimental

techniques, establish enlarged collaborations, facilitate contacts and exchange information.

The meeting participants and the IAEA representatives thanked the representatives of Germany

for hosting this event, organizing the technical tour to TRIGA Mark II reactor Mainz and their

kind hospitality during the meeting. The support and organizational effort of the IAEA was also

gratefully acknowledged.

A number of conclusions were reached regarding the current state of neutron therapy and

research. First, a description and characteristics of neutron beam facilities used for cancer therapy

were identified. For BNCT, only 2 research reactors, in Japan and Taiwan, China, continue with

clinical BNCT, following the unexpected decision to shut down the FiR-1 reactor in Finland.

Three accelerator based BNCT facilities are under final design and construction in Japan. Four

additional research reactor facilities in Argentina, Poland, Russian Federation and China are

expected to begin clinical trials in the future.

For FNT, the FRM II research reactor in Germany continues to perform this technique. Four

accelerator based facilities, two in the Russian Federation and one each in South Africa and USA

also perform clinical FNT. No new FNT facilities are planned.

Explicitly, these operational beams and facilities, including those available upon request for

patient treatment, were identified:


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FNT (5-6): FRM-II research reactor in Munich, accelerators in Tomsk, Snezhinsk, Seattle, and

Cape Town. Additional accelerator facility in Essen perhaps could be made operational if

requests for treatment were received;

BNCT (3-7): KURRI reactor in Japan, THOR reactor in Taiwan, China, and accelerator in Japan

– all 3 operational. Four additional research reactor facilities in Argentina, Poland, Russian

Federation and China are expected to begin clinical trials in the near future.

In an evaluation of the present status of neutron therapy applications, the number of BNCT

irradiated patients remain small, <1000, while for FNT, the number of irradiated patients is about

30 000.

Recent innovations and future developments in neutron therapy that may advance the techniques

are PG-SPEC for online monitoring of boron concentration in tumour cells, other more

conventional methods for monitoring of boron concentration such as PET, neutron therapy

development with target nanoparticles, and full scale Monte Carlo modelling of dose assessment

and patient treatment planning.

In terms of physical and biological dosimetry in neutron therapy, a need currently exists for well-

established protocols and standardization for irradiation procedures, boron uptake and

concentration verification, neutron fluence and spectral characterization, and dose estimates and

reporting. Integrated treatment planning for neutron therapy should also be explored.

Weighing accelerators versus research reactors for future neutron therapy, with progress in

accelerator and high power target technology, accelerator based neutron sources seem to have a

promising future in the field of neutron therapy, both FNT and BNCT. This should potentially

increase public acceptance by means of in-hospital facilities and decrease operational and

treatment costs.

Considering side effects induced by neutron therapy and possible solutions for their

minimization, present protocols in BNCT are based on respecting the maximum allowable doses

of non-tumour cells. Some important progress has been made in better control of boron uptake

and its distribution in the tumour cells, resulting in more precise irradiation protocols.

In terms of clinical and public acceptance of neutron therapy, the shift from research reactors to

accelerator based neutron sources for BNCT certainly will improve public acceptance. The public

image should be built on success stories relating irradiation parameters to positive responses in

the treatment of patients. Unique niches with considerable number of potential patients, e.g. head

and neck, and skin cancers, but for which other well established techniques are not suitable

should be identified.

Finally, to enhance the sharing of good practices and strategies for international collaboration in

the field of neutron therapy, a working group on boron concentration and uptake monitoring for


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BNCT would be useful. Also a need exists for a consensus on dose determination and reporting

both for BNCT and FNT. In case of accelerator based BNCT, further technological

breakthroughs in high power target development for neutron production (>10 kW with 9Be(p,xn)

and 7Li(p,xn) reactions and low incident energies <10 MeV) must be attained. Lessons learned

and established practices from Japan should be disseminated through networking and closer

cooperation within such organizations as the IAEA and World Health Organization.

In the case of Member States without operational neutron therapy programmes, many were

optimistic toward initiating national programmes upon proper funding and guidance from

national or supranational, e.g. the European Union, national authorities. Both accelerators and

currently operational research reactors were deemed useful. Hadron therapy was also mentioned.

Some Member State institutions were willing to develop boron carriers and drugs. International

cooperation, at least a forum to share information, progress and issues is vital to advancing

BNCT and FNT. Much work on the public awareness also needs to be accomplished.

Among those Member States operating such programmes, outreach to the medical profession and

public was found just as vital as the need for continued clinical trials. The formulation of

strategies could be simplified if institutes focus on one specific treatment rather than conducting

research and development of both BNCT and FNT. Success stories should form the basis of

campaigns and literature to overcome fear or scepticism toward neutrons. Political support could

prevent the re-occurrence of a programme shutdown, as in Finland. On the other hand, a network

among research reactor and accelerator institutes, medical hospitals, and universities would

greatly assist the survival of the community and the initiation of new platforms for cooperation.

In terms of treatment, boron uptake and analysis must continue.

REFERENCES

[1] Clare Stannard, Frederik Vernimmen, Henri Carrara, Dan Jones, Shaheeda Fredericks, Jos Hille,

Evan de Kock, Malignant salivary gland tumours: Can fast neutron therapy results

point the way to carbon ion therapy? Radiotherapy and Oncology 109 (2013) 262–268

[2] L. I. Musabaeva, V. A. Lisin, Neutron Therapy of malignant neoplasms. Tomsk (2008) 285 pages,

ISBN 978-5-89503-391-3 (in Russian)

[3] Vazhenin A V, Rykovanov G N, The Urals Center of Neutron Therapy: History, methodology and

results, Russian Academy of Medical Sciences, Moscow (2008) 142 pages (in Russian), ISBN 978-5-

7901-0094-9

[4] W. Sauerwein, A. Wittig, R. Moss, Y. Nakagawa (Eds.): Neutron Capture Therapy - Principles and

Applications. Springer 2013 (553 pages), ISBN 978-3-642-31334-9 (eBook)

[5] Rolf Barth, M Graca H Vicente, Otto Harling, WS Kiger, Kent Riley, Peter Binns, Franz Wagner,

Minoru Suzuki, Teruhito Aihara, Itsuro Kato und Shinji Kawabata: Current status of boron neutron

capture therapy of high grade gliomas and recurrent head and neck cancer. Radiation Oncology, 7(1):146

(2012), DOI: 10.1186/1748-717X-7-146

http://dx.doi.org/10.1186/1748-717X-7-146


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APPENDIX I. LIST OF PARTICIPANTS

1 Algeria S. Djaroum [email protected] 2 Argentina E.F. Boggio [email protected] 3 Austria M. Blaickner [email protected] 4 Brazil P.T.D. Siqueira [email protected] 5 Czech Republic V. Klupák [email protected] 6 Denmark N. Bassler [email protected] 7 Germany B. Al-Nawas [email protected] 8 Germany G. Hampel [email protected] 9 Germany T. L. Ross [email protected] 10 Germany T. Nawroth [email protected] 11 Germany A. Wittig [email protected] 12 Germany W.A.G. Sauerwein [email protected] 13 Germany F.M. Wagner [email protected] 14 Germany H.M. Specht [email protected] 15 Indonesia Y. Sardjono [email protected] 16 Italy S. Altieri [email protected] 17 Italy G. Gambarini [email protected] 18 Japan K. Ono [email protected] 19 Japan K. Nakajima [email protected] 20 Japan J. Itami [email protected] 21 Japan A. Matsumura [email protected] 22 Poland M.A. Gryzinski [email protected] 23 Russian Federation V.M. Golovkov [email protected] 24 Russian Federation A. A. Lipengolts [email protected] 25 Russian Federation A.A. Cherepanov [email protected] 26 United Kingdom C.L. Schütz [email protected] 27 United Kingdom D.J. Grocott [email protected] 28 USA R. Emery [email protected] 29 IAEA D. Ridikas [email protected] 30 IAEA R. Sollychin [email protected]

mailto:[email protected]































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APPENDIX II. MEETING AGENDA

Monday, 1 July 2013

08:30-09:00 Arrival of participants; registration; upload of presentation files

Session I

09:00-09:30 Welcome & Opening Address by the representative(s) of IAEA and host

organization, followed by Election of Chairperson(s) and Rapporteur(s)

09:30-10:00 1. IAEA Activities Related to Enhanced Utilization of Research Reactors;

objectives of this meeting

D. Ridikas, IAEA

10:00-10:30 2. BNCT at Thermal Beam of Multipurpose RR of the type TRIGA

G. Hampel et al., Univ. Of Mainz, Germany

10:30-11:00 Coffee break

11:00-11:30 3. Tumor-selective irradiation through BNCT: preclinical and clinical results

of compound uptake and imaging studies

A. Wittig et al., Philipps-University Marburg, Germany

11:30-12:00 4. BNCT Effects Genotoxicity on Embryonic Development

L.G. D’Agostino et al., Instituto Butantan, Brazil

12:00-12:30 5. Prescribing, Recording and Reporting BNCT: An Urgent Need for

Standards

W.A.G. Sauerwein et al., University Duisburg-Essen, Germany

12:30-14:00 Lunch break

Session II

14:00-14:30 6. Neutron Capture Therapy on Research Reactor of National Research

Nuclear University MEPhI. Facility, Preclinical Results, Future Prospects

A. A. Lipengolts et al., MEPhI, Russia

14:30-15:00 7. Neutron Capture Enhanced Fast Neutron Therapy (NCEFNT)

W.A.G. Sauerwein et al., University Duisburg-Essen, Germany

15:00-15:30 8. Treatment of head and neck cancer – challenges of multimodal therapy

B. Al-Nawas et al., Univ. Medical Centre Mainz, Germany


16:00-16:30 9. Progress in Radiobiology Studies for Neutron Therapy


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T. Kroc et al., FNAL, USA

16:30-17:00 Concluding remarks of the day from the Chairperson/Rapporteur

~17h00 Social event followed by the Hospitality Event, TBD All

Tuesday, 2 July 2013

08:30-09:00 Arrival of participants; upload of presentation files

Session III

09:00-09:30 10. Current status of accelerator BNCT at Tsukuba and considerations for

accelerator based neutron source

A. Matsumura et al., Univ. of Tsukuba, Japan

09:30-10:00 11. Experience of BNCT by KUR and Start of Clinical BNCT Trial by Small

Cyclotron Based Neutron Generator in KURRI

Koji Ono et al., Kyoto University Research Reactor Institute, Japan

10:00-10:30 12. Boron Analysis and Boron Imaging in BNCT

Ch. L. Schütz et al., Univ. of Birmingham, UK


11:00-11:30 13. New Boron-Folates for Folate Receptor Targeting in BNCT

T.L. Ross et al., Johannes Gutenberg-University Mainz, Germany

11:30-12:00 14. Neutron therapy development with target nanoparticles – B and Gd, Er

liposomes and polymer at ILL Grenoble and TRIGA Mainz

T. Nawroth et al., Johannes Gutenberg-University Mainz, Germany

12:00-12:30 15. Monte Carlo dose assessment in cell cultures after enrichment with

Gadolinium and irradiation in the neutron field of the TRIGA Mainz

M. Blaickner et al., AIT, Austria


Session IV

14:00-14:30 16. LET-Painting demonstrated on a Head and Neck cancer case

N. Bassler et al., Aarhus Univ., Denmark

14:30-15:00 17. Conception and design of the first hospital-based BNCT facility

J. Itami et al., National Cancer Center Hospital, Tokyo, Japan

15:00-15:30 18. Improvements Studies in the BNCT Research Facility at IPEN


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P.T.D. Siqueira et al., IPEN, Brazil


16:00-16:30 19. BNCT Hyperthermal B2 beam at RA-6 reactor: Dosimetric

characterization

E. F. Boggio et al., CNEA, Argentina

16:30-17:00 Concluding remarks of the day from the Chairperson/Rapporteur

~17h00 Social event followed by dinner, TBD All

Wednesday, 3 July 2013


Session V

09:00-09:30 20. Fission Neutrons for radiation therapy: Physical and biological aspects

F.M. Wagner et al., TUM, Germany

09:30-10:00 21. Fission Neutrons for radiation therapy: Clinical experience &

developments

H. M. Specht et al., TUM, Germany

10:00-10:30 22. University of Washington Medical Center Clinical Neutron Therapy

System: Status Report

R. Emery et al., Univ. of Washington, USA


11:00-11:30 23. Neutron therapy for cancer patients using the U-120 Cyclotron

V.M. Golovkov et al., Tomsk Polytechnic Univ., Russia

11:30-12:00 24. Mapping and imaging of dose and fluence in neutron fields of various

energies for FNT and BNCT

G. Gambarini et al., INFN, Italy

12:00-12:30 25. Collimator Design for BNCT Using 100kW Kartini RR and Compact

Neutron Generator

Y. Sardjono et al., BATAN, Indonesia


Session VI

14:00-14:30 26. Research activities in the field of neutron capture radiotherapy at the Triga

Mark II reactor of University of Pavia


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S. Altieri et al., Univ. of Pavia, Italy

14:30-15:00 27. The epithermal neutron beam at LVR-15 research reactor in Rez

V. Klupák et al., RC Rez, Czech Republic

15:00-15:30 28. Epithermal Neutron Source at Maria reactor

M.A. Gryzinski et al., NCBJ, Poland


16:00-16:30 29. A Proposed Collaborative Initiative to Help Boost Further Development in

BNCT

R. Sollychin, IAEA

16:30-17:00 Concluding remarks of the day by the Chairperson/Rapporteur

~17h00 Social event followed by dinner, TBD All

Thursday, 4 July 2013


Session VII

09:00-10:30 Round table discussions, drafting meeting conclusions and recommendations:

Facilitated by Chairpersons/Rapporteurs


11:00-12:30 Round table discussions, finalizing meeting conclusions and recommendations

Facilitated by Chairpersons/Rapporteurs


Session VIII

13:30-15:00 Technical tour to TRIGA Mark II reactor and its experimental facilities


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Group photo


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37

APPENDIX III. BOOK OF ABSTRACTS

1. IAEA, Ridikas

IAEA Activities Related to Enhanced Utilization of Research Reactors

D. Ridikas

Department of Nuclear Sciences and Applications

International Atomic Energy Agency,

Vienna International Centre, PO Box 100, A-1400 Vienna, Austria

[email protected]

Research reactors (RRs) have played and continue to play an important role in the development of neutron

science and related technologies, generation of radio-isotopes for medicine and industry, provision of

multi-elemental analysis of various samples, improvement of quality of materials through irradiation by

neutrons, and creation of other products and services for a broad range of applications. RRs can also be

useful tools in support of present and future national nuclear power programmes through development and

testing of new reactor concepts, new fuels or structural materials, as well as the development of human

resources and skills. Today the decreasing fleet of these facilities faces a number of critical issues and

important challenges such as underutilization, non-existent or inappropriate strategic business plans,

ageing and needs for modernization–refurbishment, presence of fresh or spent HEU fuel, unavailability of

qualified high-density LEU fuels, accumulation of spent nuclear fuel, lack of advanced decommissioning

planning, and in some cases safety and security issues. In addition to this non-exhaustive list of challenges

are the plans to build new RRs by Member States with little or no experience in this domain.

Although the number of RRs is steadily decreasing, more than half remain heavily underutilized, without a

clear purpose or strategy, and in many cases underfunded and understaffed. Keeping in mind that more

than 50% of operational RRs are more than 40 years old, the number of RRs will continue to decrease. In

this context, greater international cooperation and networking is required to ensure broader access to the

remaining facilities, including improving access for Member States without RRs, and increase their

efficient utilization. Indeed, if the benefits from RRs are to be realized, then the premises upon which they

are built and operated must be reconsidered and updated to fit today’s technical, economic and social

situation. In this respect, all aspects of RR utilization, strategy and life cycle management should be re-

examined.

The paper will highlight a number of selected efforts-examples of the recent IAEA activities in order to

address the most urgent issues and challenges in the area of RR utilization and applications. Particular

emphasis will be given to the use of neutron beams, including their application in the area of neutron

therapy.



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2. Argentina, Boggio

BNCT Hyperthermal B2 beam at RA-6 reactor: Dosimetric characterization

E.F. Boggio, J.M. Longhino

Bariloche Atomic Center (Atomic Energy National Commission)

Av. Bustillo Km. 9.5, 8400 San Carlos de Bariloche, Rio Negro, Argentina

E-mail: [email protected]

BNCT treatment facility at RA-6 reactor in Argentina was upgraded in order to enhance room for patient

positioning and comfort, ensuring proper biological shielding. Also BNCT hyperthermal beam B2 was

improved in specific irradiation parameters, namely an increase in the neutron flux intensity and extended

uniformization of the irradiation field. After physical modifications took place, an experimental dosimetric

characterization of the beam was performed. Usual activation techniques were employed to obtain thermal

and epithermal neutron fluxes, both with beam free in air and into a standard water phantom. Gamma and

fast neutron doses were measured in both configurations implementing the paired ionization chambers

method, using tissue-equivalent and graphite miniature chambers. All the results will be shown in detail,

and compared with several other techniques that have been implemented in the dosimetric characterization

process.



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3. Austria, Blaickner

Monte Carlo dose assessment in cell cultures after enrichment with Gadolinium and

irradiation in the neutron field of the TRIGA Mainz

M. Blaickner1, M. Ziegner

1,2, H. Böck

2, R. Khan

3, T. Peters

4, C. Grunewald

4, G. Hampel

4

1) AIT Austrian Institute of Technology, Health & Environment Department – Biomedical Systems,

Donau-City-Strasse 1/2, 1220 Wien - Austria

2) Vienna University of Technology, Institute of Atomic and Subatomic Physics Stadionallee 2, 1020 Wien

– Austria

3) Department of Nuclear Engineering (DNE), Pakistan Institute of Engineering & Applied Sciences

(PIEAS), P.O Nilore, Islamabad, Pakistan

4) Institute of Nuclear Chemistry, Johannes Gutenberg University of Mainz Fritz Strassmann Weg 2,

55099 Mainz – Germany


Neutron capture therapy (NCT) makes advantage of the secondary particles produced in a neutron capture

reaction in order to selectively destroy tumour cells. For this the patient is injected with a tumour

localizing tracer that carries isotopes is with a high probability of neutron absorption, such as 10

B and 157

Gd. Gadolinium has not only the advantage of the higher absorption cross section (254000 barn vs.

5830 barn for 10

B), but it is also established as contrast agent in MRI (magnetic resonance imaging). The

(n,γ) reaction of 157

Gd yields a high amount of inner conversion electrons and Auger electrons of low

energy and short range in human tissue. Therefore a very local dose deposition is possible in the case of

GdNCT (gadolinium neutron capture therapy). When it comes to dosimetry and the determination of the

relative biological effectiveness of the irradiation one has to rely on Monte Carlo methods and

experiments on biological samples. MCNP5 code is employed which is a well-established code to

simulate the transport of neutrons, electrons and photons. A detailed model of the mixed neutron/gamma

field of the TRIGA Mainz was validated and benchmarked using various phantoms and dosimeters

(TLD's, alanine dosimeters, gold activation foils) and then simplified to allow for a closer look on in vitro

experiments regarding the survival rates of cell cultures. For this purpose the Monte Carlo Modell was

extended by means of cell culture plates representing medium with different 157

Gd concentrations that are

irradiated within the thermal column of the TRIGA Mainz.

The results show that the dose deposition by the secondary electrons yielded in the 157

Gd reaction prevails

over all other dose components. This way the relation between 157

Gd concentration and cell survival can

be used to deduct factors describing the relative biological effectiveness.



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4. Brazil, Siqueira

Improvements Studies in the BNCT Research Facility at IPEN

P.T.D. Siqueira, V.A. Castro, T.A. Cavalieri, F.A. Guerra, P.R.P. Coelho

Nuclear Engineering Center, Nuclear and Energetic Research Institute, IPEN/CNEN-SP


A BNCT research facility has been projected and constructed along one of the beam holes of the IEA-R1

reactor. In order to have a thermal neutron flux intensity of the order of 108 – 10

9 n.cm

-2.s

-1, irradiation

position is inside the beam hole. The facility comprises two modules: one that stands between the reactor

core and the irradiation position, and a second one that stands downstream. The first module is intended to

hold the moderators and filters so to allow changes in the irradiation field. The second one holds the

irradiation cavity and the shielding.

To allow sample changes during reactor operation, a remote controlled system retrieves the downstream

module from the beam hole while a biological shielding, built around the beam hole opening, sustains the

working conditions in the experiment hall. Sample change is performed from the external side of the

biological shielding by a manual controlled device.

Experiments which have been planned for the near future have shown, however, the necessity to improve

irradiation conditions. These improvements shall lie both in the irradiation field – with the reduction of the

gamma contamination - and in the operational conditions – providing a better use of the irradiation cavity.

Studies have therefore been conducted to optimize the intended objectives. Field improvement studies

have been carried on with MCNP simulations run in order to get the best moderator and filter set and also

to evaluate possible changes in their geometry. Better operational conditions have been pursued by using a

remote controlled sample changer device, developing a sample specific holder and improving the

biological shielding. This last improvement is, however, planned to be executed later, in a further future.


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5. Brazil, D’Agostino-Butantan

BNCT Effects Genotoxicity on Embryonic Development

L.G. D’Agostino1, M.G.L. Silva

1, T.O. Conceição

1, V.A. Castro

2, T.A. Cavalieri

2, P.T.D. Siqueira

2,

P.R. Coelho2, D.A. Maria

1

1) Biochemistry and Biophysics Laboratory, Instituto Butantan, Sao Paulo, Brazil

2) Nuclear Engineering Center, Nuclear and Energetic Research Institute, IPEN/ CNEN-SP


The Boron Neutron Capture Therapy (BNCT) is based on the nuclear capture and fission reactions of the 10

B nucleus with low energy thermal/epithermal neutrons to yield high linear energy transfer alpha

particles and recoiling 7Li nuclei reaction (Q = 2.8 MeV). Since the path lengths of the particles are

approximately 9 to 10 µm. 10

B-containing cells are selectively destroyed by BNCT. The effect of BNCT

irradiation on angiogenesis and embryo genotoxicity was studied in incubated eggs lying on a hatching

tray. Eight white eggs of Gallus domesticus, aged approximately 240 days were incubated in an automatic

incubator with thermostat. The BNCT group was irradiated at the BNCT research facility at the IEA-R1

nuclear research reactor in IPEN. The eggs were irradiated for 5 and 15 minutes under a thermal neutron

flux of around 5x108 n.cm

-2.s

-1. The incubation was carried at 37.2ºC, relative humidity (60%), with the

automated periodical turns at two hour intervals, for the control and BNCT groups exposed eggs. Viability

in the closed shell eggs was observed during the early embryo development with the help of the ovoscope.

Incubation proceeded until the 20th day, for survival evaluation of one exposed egg plus its control. The

chorioallantoic membrane (CAM) sampling was done on the 11th day, for the CAM vasculature analysis.

In the 11th day, the eggs were placed for at least 20 minutes at 4°C before being opened. The shells were

cut in the air chamber and a few formalin droplets were added over the exposed CAM membrane and left

for 5 minutes. The BNCT caused significant morphology changes on the CAM vessels. It was possible to

observe intact capillary networks. However, there were micro obstructive effects that partially impair the

minor vessel replenishment, low the connectivity of the capillary web and increase the congestion of the

higher order vessels. Besides, the venules and capillaries were tortuous and also with decreased diameters.

Macroscopic examination of the fetus in the 11th day of incubation revealed preserved crown rump

dimensions and general aspect with significant effects upon muscle mass and embryo viability. BNCT

results in a highly complex dose distribution with different dose components having different biological

effects on CAM model. The toxic effects BNCT and embryo genotoxicity occurred without loss of

embryo viability and were associated with the partial preservation of the capillary diameters and

connectivity.



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6. China, Li (not presented)

Measurement of Neutron Parameters in the Neutron Beams of the In-Hospital Neutron

Irradiator

Li Yiguo, Lu Jin, Peng Dan, Zou Shuyun Wu Xiaobo, Hong Jingyan

China Institute of Atomic Energy, Beijing,102413,China


The In-Hospital Neutron Irradiator (IHNI) is specially used for Boron Neutron Capture Therapy(BNCT).

On the both sides of the reactor core, there are two neutron beams, one is thermal neutron beam , and the

other opposite to the thermal beam, is epithermal neutron beam. A small thermal neutron beam is specially

designed for the measurement of blood boron concentration by the prompt gamma neutron activation

analysis (PGNAA).

In this paper, some parameters at the exit of neutron beam, such as, the absolute neutron flux, neutron flux

distribution, neutron spectrum, are measured by gold(Mn) foil activation method, solid state nuclear track

detector (SSNTD) method.

The measuring results are : the absolute neutron flux of the thermal neutron beam is 1.61×109n/cm

2·s by

Gold foil activation method，and 1.50×109n/cm

2·s by solid state nuclear track detector method；Neutron

fluxes at the exits of epithermal neutron beam and small thermal neutron beam are 2.20×107n/cm

2·s and

2.91×106n/cm

2·s respectively by solid state nuclear track detector method. The neutron spectrum is

measured by multiply foils activation method and unfolded by SAND-II program.

The discrepancy distribution of thermal beam is less than 8% in the area of R<3cm in the centre of the exit

,while the discrepancy distribution of Epithermal beam is less than10% in the area of R<3cm; the percent

of thermal neutron in the total neutron is over 90% in the exit of thermal neutron beam. The results show

that the neutron beams of the IHNI can meet the designed requirements, and can be used for BNCT.



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7. Czech Republic, Klupak

The epithermal neutron beam at LVR-15 research reactor in Rez

V. Klupák, L. Viererbl, J. Burian, M. Marek, M.Vinš

Research Centre Rez, Husinec - Řež, čp. 130, 250 68 Řež, Czech Republic


The nuclear research reactor LVR-15 is a multipurpose facility used for nuclear engineering applications,

radiopharmaceuticals and radioisotopes production, material testing, and basic and applied research. The

reactor is equipped (besides other things) with ten horizontal and several vertical irradiation channels. One

of the horizontal channels is also an epithermal neutron beam which was completed in year 2000 for

purpose of a research in the field of boron neutron capture therapy. In 2003, the BNCT research at the

LVR-15 reached its peak as a group of patients was treated in the project “Pre-clinical trials of brain

tumours” using the method of Boron Neutron Capture Therapy (BNCT). At present, the beam main

utilization is still for the study of biological aspects of BNCT (the in-vivo irradiation of living mice), but it

is also used as a source of epithermal neutrons for testing detectors and electronic devices in mixed

neutron-photon field. Besides that, several original experiments were carried out at BNCT beam during

the last years.

The paper describes main characteristics of the LVR-15 epithermal neutron beam facility and it

summarizes activities and measurements performed during its operation.



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8. Germany, Al-Nawas

Treatment of head and neck cancer – challenges of multimodal therapy

B. Al-Nawas

University Medical Center Mainz; J. Gutenberg University, D-55131 Mainz


The estimated incidence of cancers of the oral cavity and pharynx in varies from 46/100,000 for men

in Hungary to 4.3/100,000 in Cyprus. Malignant tumours of the oral cavity, lip and throat are

accounting for 5% of all tumours in Germany. The 5 year survival rate of about 50% has not

considerably changed in the last years. This narrative review will reflect the different therapy

modalities and line out the role for neutron therapy of squamous cell head and neck cancer (SCHNC).

Surgery up to now remains the major therapy strategy in SCHNC. Classical approach consists of

surgery as a first line therapy, which might be followed by classical radiotherapy (tele-therapy) and in

some cases chemotherapy. Promising studies (DELOS I & II) are under investigation, which support

older concepts of neo-adjuvant radio-chemotherapy followed by surgical resection. Especially for

functional organ preservation in laryngeal and tongue cancer these concepts are of importance.

Modern radiotherapy concepts (IMRT) have helped to decrease the rate of radiotherapy related side

effects, like radio-xerostomia or osteoradionecrosis. Nevertheless the affection of the salivary glands

still represents a major long term problem of patients with SCHNC. More recently EGFR receptor

antagonists have been developed and are in use in the adjuvant and in the palliative setting. The use of

these substances is limited by skin reactions. Especially after a relapse therapy options are limited.

Brachytherapy is a promising but invasive therapy option. Boron-Neutron Capture Therapy has been

shown to be effective also in these palliative situations, were classical therapy options are limited and

may help to regain Quality of Life for patients with advanced stage or relapse of SCHNC. The

possible clinical role of BNCT will be outlined in the presentation.

Further development of these techniques will help to individualize tumour therapy and increase both

Quality of Life and survival after tumour therapy.



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9. Germany, Ross

New Boron-Folates for Folate Receptor Targeting in BNCT

K. Kettenbach, H. Schieferstein, C. Grunewald, D. Iffland,

C. Schütz, G. Hampel, T.L. Ross

Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, 55128 Mainz, Germany


The boron neutron capture therapy (BNCT) in based on 10

B-pharmaceuticals, which should ideally

accumulate in tumour tissue only and which are subsequently irradiated by thermal neutrons. The resulting

nuclear reaction 10

B(n,α)7Li provides a high-energy α-particle and a

7Li-nucleus. Both deposit their energy

with a very high LET (linear energy transfer). Due to their low range of only 5-9µm (below one cell

diameter), they leave a high local dose in tumour cells. The so far clinical established boron phenylalanine

(BPA) or sodium boron mercaptate (BSH) only use inefficient (BPA) or passive (BSH) targeting for

accumulation in tumour tissue. The folate receptor alpha (α-FR) is (over)expressed on many human

carcinomas and provides a selective and specific target for molecular imaging as well as for tumour

therapy. The aim of this work is the combination of BNCT with the highly efficient folate targeting.

A γ-boron-folate was regioselectively synthesized via the Cu(I)-catalyzed click cycloaddition at the γ-

position of the glutamic acid moiety of folic acid. On the other hand, an alkyne-maleimidecarborane and -

BSH was prepared via a thiol-en reaction of the carborane-, respectively BSH-cluster with alkyne-

maleimide. In a last step the protected folic acid underwent an alkaline deprotection. The obtained boron

folates were tested concerning their uptake in human KB cells. Both boron-folates were used in different

concentrations and at varying incubation times. The content of boron in KB cells and the receptor-bound

fraction were measured with ICP-MS and -OES.

We successfully synthesized two different boron-folates, a carborane and a mercaptoborane folate. The

first cell uptake studies show very promising results with a clear increase of boron uptake compared to the

clinical established BPA.

The efficient and specific accumulation of the new boron-folates via folate receptor targeting allows a

highly effective accumulation, which should enable to lower the amount of systemic administered boron

pharmaceutical. Due to these promising results, radiation experiments at the TRIGA reactor in Mainz and

treatment studies in animal models are planned.

[1] Barth, R F et al. 2012, Radiat Oncol 7, 146; [2] Müller, C, Schibli, R 2011, J Nucl Med 52, 1.



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10. Germany, Hampel

Boron Neutron Capture Therapy (BNCT) at the thermal beam of a multipurpose research

reactor of the type TRIGA

G. Hampel1, B. Al-Nawas

2, N.H. Bings

3, M. Blaickner

4, H. Lang

5, P. Langguth

6, T.

Ross1, G. Otto

7

1. Institute for Nuclear Chemistry, University of Mainz, D-55099 Mainz, Germany 2. Department of Oral and Maxillofacial Surgery, University of Mainz, D-55099 Mainz, Germany 3. Institute for Inorganic and Analytical Chemistry, University of Mainz, D-55099 Mainz, Germany 4. AIT Austrian Institute of Technology GmbH, A-1190 Vienna, Austria 5. Clinic of visceral and Transplantation Surgery, University of Mainz, D-55099 Mainz, Germany 6. Department of Pharmacy and Toxicology, University of Mainz, D-55099 Mainz, Germany 7. Department of Hepatobiliary, Pancreatic and Transplantation Surgery, University of Mainz, D-

55099 Mainz, Germany Current research efforts in BNCT are focussed on boron compounds, radiobiology and pharmacology,

dosimetry and treatment planning, and improvement of boron analysis using methods such as Prompt

Gamma Activation Analysis (PGAA), Autoradiography, Inductively Coupled Plasma Mass Spectrometry

(ICP-MS) and Inductively Coupled Plasma Optical emission Spectrometry (ICP-OES) and the

visualisation of the boron compound by Magnetic Resonance Imaging (MRI) or Positron Emission

Tomography (PET). For the second topic, knowledge to better understand the transport behaviour of the

carrier molecules into different kinds of cells, into which cell compartments and on the pharmacokinetics

of the boron compound, help towards increasing the 10

B concentration in the tumour. Pharmacokinetics

modelling and simulations are important tools to predict the 10

B concentration and tumour dose.

Irradiation studies using different cell lines deliver information about the RBE value. For patient

treatment, it is crucial to have a reliable and formally-recognised dosimetry system. Radiation facilities for

BNCT in most cases are still centred on a research reactor, while new accelerator-based ones are under

development. It would be advisable that if a new research reactor was to be built, then the capability for

BNCT appliucations can be included in the design. Most existing reactors, however, were designed before

concept of BNCT and generally have to be modified to fulfil the requirements as a treatment facility for

BNCT.

The research reactor TRIGA Mark II of the University of Mainz, Germany, is intensively used for basic

research in physics and chemistry, applied science and educational purpose. The reactor can be operated in

the steady state mode with the thermal powers up to a maximum of 100 kW and in the pulse mode witj a

maximum peak power of 250 MW. In addition to the in-core irradiaton positions, the reactor includes four

horizontal beam ports and a graphite thermal column providing a source of well-thermalized neutrons

which is used extensively and very effectively for research in BNCT. The radiobiological, pharmaceutical

and clinical research takes place at the University and also at the University Hospital. Both are situated in

close vicinity to each other, which is an ideal situation for BNCT treatment.

The idea to implement a BNCT project at the TRIGA Mainz was due to the pioneering work at the

TRIGA in Pavia (Italy), where patients with liver metastases were treated successfully in 2001 and 2003.


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47

Extended involvement of the liver by primary and secondary cancer is life limiting even if the tumour is

confined to thi organ. So far in this situation only palliative treatment using chemotherapy is applicable.

The BNCT group Mainz is now a multinational research consortium and is conducting research into

BNCT to explore the possibilities of a curative treatment of the liver, as well as in fundamental research in

BNCT including the subjects mentioned above.

The reactor facility, while obviously important, is only one part of a very large and necessary

infrastructure for the performance of neutron-based therapy. Most importantly, the key factor for success

in BNCT in future is the collaboration between very different disciplines: radiation oncology, surgery,

pathology, nuclear physics, chemistry, pharmacology, radiation biology and mathematics.


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48

11. Germany, Nawroth

Neutron therapy development with target nanoparticles – B and Gd, Er liposomes and

polymer at ILL Grenoble and TRIGA Mainz

T. Nawroth1a

, T. Peters1a

, P. Langguth1a

, K. Grunewald1b

, G. Hampel1b

, H. Schmidberger1c

, R.

Schweins2

1) Gutenberg-University a) Pharmacy,Staudingerweg5, b) TRIGA reactor, Becherweg, D-55099 Mainz;

c) University Medicine, Radiooncology clinics, Langenbeckstr.1, D-55101 Mainz

2) Institut Laue Langevin, LSS, Avenue des Martyrs, F-38043 Grenoble


We report on our development on target nanoparticles a) entrapping Boron, Gadolinium and Erbium, and

cell targeting with surface modification. The particles of 100 nm size are liposomes and biodegradable

polymer particles, where we have just got an European patent (Lanthanide loaded polymer NP for

radiotherapy [1]). Similar particles are used for neutron therapy (NCT) and photon therapy (ESRF,

clinics). The particles are characterized with neutron scattering SANS (ILL-D11, -D22), synchrotron x-ray

scattering SAXS (ESRF, BESSY), metal specific ASAXS (BESSY and ESRF) , dynamic light scattering

DLS, and SANS-DLS double beam investigation [3]. For the therapy tests we have developed a time

resolved cell culture system as tumour model, which we call EPN test (exponential necrosis and

proliferation test). This distinguishes between direct cell destruction, and the clinically wanted

proliferation inhibition with delayed apoptosis, which corresponds in therapy to tumour growth stop and

regression. The photon therapy tests were done at the K-edges of the metals at ESRF-ID17 (biomedical

facility), and the radio therapy clinics Mainz with a linear accelerator (8 MeV); the neutron therapy tests

with cold neutrons at the ILL (D22), Grenoble, and with thermal neutrons at the TRIGA reactor Mainz.

Beam time at the FRM-2 reactor Munich is on schedule. The aim of the current development is a case and

person specific therapy with local target enrichment at cell level. This is done by fast surface coupling of

cell receptor ligands with linkers using click chemistry and material banks. The project is funded by the

German Ministry of Science and Education BMBF, grant 05KS7UMA.

1. European patent EP 2 567 702 A1 , WIPO – PCT WO 2013/037487 A1 ; Johannes Gutenberg-University,

with inventors : P Langguth, K Buch, T Nawroth, H Schmidberger

2. K Buch, T Peters, T Nawroth, M Sänger, H Schmidberger, P Langguth (2012) Radiation Oncology 7, 1-6

3. T Nawroth, P Buch, K Buch, P Langguth, R Schweins (2011) Mol. Pharm. 8, 2162-72



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12. Germany, Wittig

Tumor-selective irradiation through BNCT: preclinical and clinical results of compound

uptake and imaging studies.

Andrea Wittig1, Raymond Moss

2, Wolfgang Sauerwein

3

1) Dept. of Radiotherapy and Radiooncology, Philipps-University Marburg, Baldingerstrasse, 35043

Marburg, Marburg, Germany

2) HFR Unit, Institute for Energy, JRC, European Commission, Petten, The Netherlands

3) NCTeam, University Duisburg-Essen, University Hospital Essen, Hufelandstrasse 55, 45122 Essen,

Germany


BNCT uses the high cross section of 10

B to capture thermal neutrons resulting in a nuclear reaction, which

produces high LET He- and Li-nuclei. The short range of these particles in tissue limits the biological

effects of this radiation to a single cell, which hypothetically allows for a radiotherapy, which is targeted

on the cellular level. In the last years, prerequisites for a successful clinical application of BNCT were

optimized: Accelerator based neutron sources are becoming available, the quality of the 2 drugs that can

be used in clinical trials has been improved and the knowledge of their biological properties has been

enlarged. In animal experiments, we found mean 10

B-concentration ratios between tumour and normal

tissues above 4.5 after BSH-injection between: melanoma/brain (6.4±6.1), murine sarcoma/brain

(17.9±8.2), murine sarcoma/muscle (8.6±3.3), adenocarcinoma/brain (12.9±6.9), adenocarcinoma/muscle

(8.6±10.2), human sarcoma/brain (8.4±6.8), human sarcoma/muscle (7.2±3.2). After BPA-injection ratios

above 4.5 were observed between: adenocarcinoma/brain (4.5 ± 2.7), murine sarcoma/brain (5.2±0.6),

glioblastoma/muscle (4.8±7.5), glioblastoma/brain (6.5±3.8).The combined injection of BPA and BSH led

to high ratios between: melanoma/brain (5.0±2.8), murine sarcoma/brain (6.3±1.6) and glioblastoma/brain

(5.4±1.3). The selective action of BNCT may especially lead to an advantage where relatively radio-

resistant cancer cells invade healthy structures (e.g. malignant glioma) and in recurrent tumours, which are

pre-treated with conventional radiotherapy. The high LET component may allow to successfully treating

radio-resistant tumours (e.g. melanoma, sarcoma). Results of the in vivo uptake trials support further

optimization of BNCT for these entities. Equally important is further development of methods to evaluate

the 10

B concentration and distribution in tissues and cells. Available methods to detect and image 10B in

biological samples will be presented and discussed.



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13. Germany, Sauerwein-1

Neutron Capture Enhanced Fast Neutron Therapy (NCEFNT)

W.A.G. Sauerwein1, J.-P. Pignol

2, J.P. Slabbert

3, R. Moss.

4, L. Brualla

1, A. Wittig

5

1) University Duisburg-Essen, University Hospital Essen, NCTeam Strahlenklinik, Hufelandstr. 55,

45122 Essen (Germany)

2) University of Toronto, Sunnybrook Health Sciences Centre, Dept. of Radiation Oncology,

2075 Bayview Avenue, ON M4N 3M5 Toronto (Canada)

3) iThemba LABS, P.O. Box 722, Somerset West 7129 (South Africa)

4) European Commission, Joint Research Center, Westerduinweg 3, 1755 ZG Petten (The

Netherlands)

5) Philipps-Universität Marburg, Klinik für Strahlentherapie und Radioonkologie, Baldingerstrasse,

35043 Marburg (Germany)


Purpose: Fast neutron therapy (FNT) is an established clinical modality taking advantage from the high

Linear Energy Transfer properties (LET) of this radiation resulting in increased biological effects. In the

last 2 decades progress in radiation oncology was essentially made by increased precision using optimized

beam delivery systems for photons and dose localization properties of charged particles. Nowadays, the

proven superiority of FNT in specific situations is contested because of their physical properties

challenging a highly precise dose delivery. Fast neutrons are thermalized at depth and are then able to

produce neutron capture reactions such as 10

B(n,7Li or

6Li(n,)

3H. Assuming compounds delivering

these isotopes selectively into tumour cells a highly conformal delivery of high LET irradiation can be

produced by FNT at depth, were the target volume is localized.

Methods: Using the FNT facility at the University Hospital Essen, a multitude of preclinical in-vitro and

in-vivo experiments have been performed using 3 different cell lines (MeWo, Be-211 and PECA) and the

murine Harding-Passey melanoma on BALB/c mice.

Results: The thermal fluence rate at 5 cm depth using a 20x20 fast neutron beam was 13 x 107 cm

-2s

-1. A

significant increase of all radiation effects was shown in presence of 10

B or 6Li, i.e. a decrease of cell

survival, but also an increase of high LET effects [increase of from 0.76 Gy-1

(fast neutrons) to 3.47 Gy-

1(NCEFNT) or decrease of Oxygen Enhancement Ratio from 2.1 to 1.6]. A dramatic and significant

improve of survival and local tumour control was proven in the animal experiments after addition of 10

B.

Conclusion: Compounds that were developed for NCT can be applied in FNT to increases the dose to the

target volume at depth, leading to an additional and conformal high LET irradiation to the tumour. In

addition, the thermalization of neutrons protects superficial parts of the body, i.e. the skin, which is a

dose-limiting organ for BNCT using the compound BPA. The available data allows the start of clinical

phase I trials – if financial support is becoming available.



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14. Germany, Sauerwein-2

Prescribing, Recording and Reporting BNCT: An Urgent Need for Standards

W.A.G. Sauerwein1, J. Rassow

1, A. Wittig

2, P. Munck, A.F. Rosenschöld

3, W.S. Kiger

4,

H. Kumada5

1) University Duisburg-Essen, University Hospital Essen, NCTeam Strahlenklinik, Hufelandstr. 55,

45122 Essen (Germany)

2) Philipps-Universität Marburg, Klinik für Strahlentherapie und Radioonkologie, Baldingerstrasse,

35043 Marburg (Germany)

3) Department of Radiation Oncology, Ringshospitalet, Blegdamsvej 9, Copenhagen, DK-2100

(Denmark)

4) Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical

School, 330 Brookline Avenue, Boston MA 02215 (USA)

5) Faculty of Medicine, Proton Medical Research Center, University of Tsukuba, 1-1-1 Tennodai,

Tsukuba, Ibaraki 305-8575 (Japan)


Absorbed dose is the fundamental quantity used in all therapeutic applications of ionizing radiation. The

absorbed dose is the basic information for understanding radiation effects and for reproducing treatment

procedures. Prescribing, recording and reporting dose in conventional radiotherapy with photons and

electrons but also in Fast Neutron Therapy (FNT) is well understood and standardized worldwide. This is

not the case for Boron Neutron Capture Therapy (BNCT). BNCT results a highly complex dose

distribution, which consists of 4 different dose components with different Linear Energy Transfer (LET)

properties and therefore different biological effects. The contributions of these different components

change with depth; they have different spatial distributions. Such a situation cannot be described with one

single number, as is the case in conventional radiotherapy. Unfortunately, solutions proposed in the past

[1-4] are not widely accepted. As a result, published data on doses are often incomprehensible and

sometimes misleading.

Accelerator-based BNCT will allow treating a high number of patients, facilitating evaluation of the pros

and cons of this modality with high statistical power. A common language for dose prescribing and

reporting is mandatory for such an evaluation. With the goal of establishing standardized procedures, we

suggest creating a panel of experts to prepare a draft for prescribing, recording and reporting BNCT for

discussions on international boards such as IAEA and ICRU.

1. W. Sauerwein, et.al.: Considerations about specification and reporting of dose in BNCT. In: Advances in

Neutron Capture Therapy Volume II (eds.: Larsson B. et al.). Elsevier, Amsterdam 1997, pp. 531-534

2. A. Wambersie, R. et.al.: Dose and volume specification for reporting NCT: An ICRU-IAEA initiative.

IAEA-TECDOC-1223, 2001, pp. 9-10



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3. J. Rassow et al.: Advantage and limitations of weighting factors and weighted dose quantities and their units

in boron neutron capture therapy. Med. Phys. 31 (2004), pp. 1128-1134

4. J. Rassow et al.: Prescribing, recording and reporting of BNCT. In: Neutron Capture Therapy - Principles

and Applications (eds.: Sauerwein W. et al.). Springer Heidelberg, 2012. pp. 277-285


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15. Germany, Wagner

Fission Neutrons for radiation therapy: Physical and biological aspects

F.M. Wagner1, H. Breitkreutz

1, P. Kneschaurek

1, J. Wilkens

3,W. Petry

1

J. Kummermehr2, E. Schmid

2, K.-R. Trott

3

1) Technische Universität München (TUM), Forschungs-Neutronenquelle Heinz Maier-Leibnitz (FRM II),

85747 Garching, Germany2) University of Munich, Department for Anatomy and Cell Biology, 80336

München, Germany

3) Technische Universität München, Klinikum rechts der Isar, Department of Radiation Oncology, 81675

München, Germany


Teletherapy by fission neutrons was performed at three research reactors: the fast reactor BR10 at Obninsk

(Russia) with mean energy 0.85 MeV as well as at FRM I and FRM II at Garching/Munich (Germany)

with mean energy 1.85 MeV each. FRM I and BR10 were closed in 2000 and 2002, respectively, but

neutron therapy was resumed at FRM II in 2007 under the medical auspices of the clinics of TUM. Since

1985, about 1700 patients have been treated at the three reactors. At FRM II, the source of radiation is a

pair of uranium plates in which fission is induced by reactor neutrons (converter). The horizontal beam is

filtered with lead to reduce the photon component to 25 % of the total dose. A multileaf collimator (MLC)

allows for fields from 6x6cm² to 30x20cm². A new MLC is under development, further a dose calculation

program on the basis of the Monte-Carlo code MCNPX.

The therapy beam at FRM II was characterised by quantitative biological dosimetry using a variety of

endpoints in order to define their anti-tumour potential. The latest investigations were performed using the

human cancer cell line UTSCC-5, grown as so called megacolonies, i.e., quasi-epithelial plaques which

ensure close intercellular contact before, during and long after treatment when radiation damage becomes

gradually expressed. The endpoints comprise responses typical for tumours in situ such as megacolony

cure and regrowth delay, but also outgrowth of surviving clonogens. Measurements of cell kill and RBE

up to 8cm depth in a PE phantom will be presented, along with results obtained by conventional colony

forming assays. Another line of investigations dealt with the formation of di-centric chromosomes in

human lymphocytes; this method is the gold standard in biological dosimetry.

Typical for the beam are high RBE values and a rapid fall-off of neutron dose rate with depth in tissue.

The resulting steep gradient in effectiveness precludes treatment of deep-seated tumours, but also provides

increased sparing of normal tissue underlying the malignancy.


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16. Germany, Specht

Fission Neutrons for radiation therapy: Clinical experience & developments

H.M. Specht1, W. Reuschel

1, R. Thamm

1, B. Loeper

1, F.M. Wagner

2, T. Auberger

3, P. Lukas

4,

M. Molls1

1) Technische Universität München (TUM), Klinikum rechts der Isar, Department of Radiation Oncology,

81675 München, Germany

2) TUM, Forschungs-Neutronenquelle Heinz Maier-Leibnitz, 85747 Garching, Germany

3) Klinikum Traunstein, Department of Radiation Oncology, 83278 Traunstein, Germany

2) Universität Innsbruck, Department of Radiation Oncology, 6020 Innsbruck, Austria


Background: Due to the high RBE (Relative biological effectiveness) neutron beam therapy might offer

an advantage when compared with photon beam therapy, especially in the treatment of malignancies that

are known to be radio-resistant. In Munich we had the chance to study the safety and efficiency of neutron

treatment by using fast reactor neutrons and applying a comparatively low total radiation dose.

Material and methods: 715 patients were treated between 1985 and 2000 at the research reactor FRM I

with fission neutrons alone or in combination with photons. In a few publications we could report on our

clinical results (e.g. Bremer et al., Radiation Oncology Investigations, 1999; Auberger et al., Recent

Results Cancer Res., 1998). In 2007 we started neutron treatment at the new reactor FRM II, which

offered improved patient facilities as well as improved physical treatment possibilities. These are

explained in more detail by the abstract of Wagner FM et al.

Results: Most of the patients treated at FRM I were suffering from Head and Neck cancer (34%),

recurrent breast cancer (26%) and cancer of the salivary glands (16%). Treatment at FRM II offers the

following advantages compared with treatment at FRM I: A multi-leaf collimator, increased maximum

irradiation field size (30x20cm), a 3-fold higher dose rate (Gy per min) leading to shorter irradiation time

and improved 3-D patient positioning by a motorized couch. The patients who have been treated until now

were suffering from recurrent breast carcinoma (38%), squamous cell carcinoma of the head and neck

(20%) or malignant melanoma (17%). An analysis of 44 patients irradiated between 2007 and 2010

showed relatively good tumor response (60% clinical remission) and low grade IV side effects (<10%).

The most commonly used treatment schedule at FRM II was a single dose of 2 Gy up to a total dose of 10

Gy applied within approximately 3 weeks (equals a photon dose of 35.6 Gy assuming a RBE=3 and

α/β=3). Mostly these patients were treated in palliative intention.

Conclusions: Treatment with reactor fission neutrons is limited due to the relatively low penetration depth

of the beam. Therefore in most cases, therapy is limited to superficial lesions as they often occur in

recurrent breast cancer at the thoracic wall or in recurrent malignant melanoma (skin lesions). To measure

the treatment success in these palliation concepts, determination of the overall survival or progression free



Working Document

55

survival might not be an appropriate tool. We observed some dramatic improvements in terms of local

tumour regression with relatively low side effects, which lead to improved quality of live and a reduced

effort for wound management for the individual patients. So further studies should also focus on criteria

like quality of life or cost effectiveness to measure the usefulness of fission neutron therapy.


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56

17. Indonesia, Sardjono

Collimator Design for Boron Neutron Capture Therapy Using 100 kW Kartini Research

Reactor and Compact Neutron Generator

Y. Sardjono

1, W. Setiawan

1, I.W. Puradwi

1, Widarto

1, Taxim

1, A. Widhiharto

2, Suharyana

3, D.A,

Musadad4, E. Meiyanto

5 and M. Syafari

6

1) Center of Accelerator and Material Process Yechnology, National Nuclear Energy Agency –BATAN,

Indonesia

2) Department of Physics Engineerung, Faculty of Engineering, Gadjah Mada University – UGM,

Indonesia

3) Department of Math and Natural Science, Surakarta State University –UNS-, Indonesia

4) Center for Public Health Intervention Technology, National Institute of Health Research and

Development, Minister of Health, Indonesia

5) Faculty of Pharmacy, Gadjah Mada University –UGM, Indonesia

6) PT Kimia Farma Tbk Indonesia

Boron Neutron Capture Therapy (BNCT) is an advanced form of radiotherapy technique that is potentially

superior to all conventional techniques for cancer treatment, as it is targeted at killing individual cancerous

cells with minimal damage to surrounding healthy cells. After decades of development, BNCT has

reached clinical-trial stages in several countries, mainly for treating challenging cancers such as malignant

brain tumours. The Indonesian consortium will invite to cooperation and be a part of and play a key role in

a global partnership on BNCT. The main objective of the global partnership are the development if BNCT

technology package which consist of a portable neutron source based on compact neutron generator

technique, advanced boron-carrying pharmaceutical, and user-friendly treatment platform with automatic

operation and feedback systems as well as commercialization of BNCT though franchised network of

BNCT clinics worldwide. The Indonesian consortium will offering to participate in Boron carrier

pharmaceuticals development and testing, development of compact neutron generators and provision of

neutrons from the 100 kW Kartini Research Reactor to guide and to validate compact neutron generator

development.

There are six beam-ports at the 100 kW Kartini Research Reactor and two of them have been studied. The

study of collimator design for BNCt at subcritical and tangential beam-port has been performed. The study

used MCNP 4C code to compute and assess the interactions between neutron and collimator materials.

Consist of collimator materials were selected i.e. graphite, lead and boron which used for illuminator,

beam filter and aperture respectively. The parameters studied are varying the thickness of illuminator and

beam filter. The result of epithermal and thermal neutron flux from collimator at subcritical beam-port are

5.9x109 and 7.1x10

7 n cm

-2s

-1. The gamma ray contaminations at subcritical and tangential beam-ports are

8x10-3

mRs-1

, 4.5x10-4

mRs-1

respectively. According to these results, it can be concluded that both beam-

port are suitable to use BNCT experiments.


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18. Italy, Altieri

Research activities in the field of neutron capture radiotherapy at the TRIGA Mark II

reactor of University of Pavia

S. Altieri1,2

, S. Bortolussi1,2

, N.Protti1,2

, I. Postuma1,2

, F.Ballarini1,2

, P. Bruschi2, E.Giroletti

1,2, A. De

Bari1,2

1) National Institute for Nuclear Physics (INFN), section of Pavia, via Bassi 6, 27100 Pavia, Italy

2) Department of Physics,University of Pavia, via Bassi 6, 27100 Pavia, Italy


University of Pavia has a long tradition in the research concerning the application of neutron radiation to

medicine, in particular in the radiotherapy exploiting neutron capture. After many years of preclinical

activity performed in vitro and in vivo on animal models, at the beginning of 2000 the neutron capture

therapy was applied to two patients affected by disseminated hepatic metastases that were not surgically

operable. After an infusion of BPA-Fructose, the liver of the patient was explanted and irradiated for 10

minutes in the irradiation facility designed on purpose and constructed inside the Thermal Column of the

TRIGA. Finally, the organ was re-implanted in the patient. Presently, the research is very active at a

preclinical level to extend the application of Boron Neutron Capture Therapy (BNCT) to other diffuse

tumours as limb osteosarcoma, pulmonary tumours and mesothelioma, using extracted neutron beams. A

strong collaboration has been built between researchers of Italian National Institute for Nuclear Physics

(INFN), different Italian Universities and some international institutions and laboratories working in

various aspects of BNCT : from the development of new boron carriers, more selective that the ones

currently employed, to boron concentration measurements in biological samples by alpha spectrometry, to

toxicity and effectiveness tests of the new carriers performed both in vitro and in vivo. An irradiation

position with low gamma background dedicated to the irradiation of cell cultures and small animals has

been characterized with neutron activation techniques, both dosimetric and microdosimetric. In particular,

in collaboration with Idaho National Laboratory (USA) it has been conducted an inter-calibration of the

performances of the irradiation facility in Pavia and of some others in international centres. In the talk, the

updated state of the art of these research activities in Pavia will be presented.



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19. Italy, Gambarini

Imaging and mapping of dose and fluence in neutron fields of various energies for BNCT

and FNT

G. Gambarini1, A. Fazzi

2, S. Agosteo

2, A. Pola

2, F. d’Errico

3, J. Burian

4

1) Department of Physics, Università degli Studi di Milano and INFN, via Celoria 16, 20133Milan, Italy

2) Department of Energy, Politecnico di Milano and INFN, via Ponzio 34/3, 20133 Milan, Italy

3) Dipartimento di Ingegneria Civile e Industriale, Università di Pisa, Largo L. Lazzarino 1,

56122 Pisa, Italy and Yale University, School of Medicine, New Haven, CT, USA

4) Department of Neutron Physics, Research Centre Řež, Ltd., Czech Republic


Methods developed for measuring the spatial distribution of absorbed dose and thermal neutron fluence

and for microdosimetry are presented.

Absorbed dose distributions in BNCT neutron fields, with separation of the various contributions, are

attained by means of suitably designed Fricke-Xylenol-Orange gel dosimeters. Absorbed dose images are

obtained by visible light transmittance images detected, before and after irradiation, by a CCD camera. By

placing dosimeters with different isotopic content in the same geometry in a tissue equivalent (TE)

phantom, it is possible to obtain, by applying suitable algorithms, the images of the various dose

components: the therapeutic dose from 10

B reaction, the photon dose and the neutron dose. From boron

dose images, by means of kerma factors, thermal neutron fluence images are attained. In order to avoid

perturbing neutron transport by changing the dosimeter isotopic composition, dosimeters are in form of

layers (3 mm thick, with square, rectangular or circular shape and maximum wideness of 18 cm) or of thin

cylinders of plastic tubes having 3 mm of external diameter.

The microdosimetric spectrum at given depths in a TE phantom irradiated by fast neutrons is accessed by

means of a silicon device. It consists of a silicon thin diode (2 μm in thickness) for the micrometric site,

coupled to a thick diode (500 μm in thickness), the latter playing a fundamental role for tissue-equivalence

correction. Satisfactory comparisons with a TEPC have been performed at the INFN-Legnaro Labs.

(Padua, I) in monoenergetic neutron fields. For the characterisation of neutron beams of energy between

0.3 and 8 MeV a neutron spectrometer has been recently developed. It consists of a compact silicon recoil-

proton spectrometer coupled to a 1 mm thick polyethylene converter. The gamma background is

effectively discriminated by proper ΔE/E proton identification. This neutron spectrometer has proven its

features in a recent campaign aiming at measuring the yield of some reactions.



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20. Japan, Matsumura

Current status of accelerator BNCT at Tsukuba and considerations for accelerator based

neutron source

A. Matsumura1, H.Kumada

2, M.Yoshioka

3, M.Yoshioka

3, Y.Kiyanagi

3, H. Nakashima

4

1) Department of Neurosurgery, Faculty of Medicine, University of Tsukuba

2) Proton Medical Research Center, University of Tsukuba

3) High Energy Accelerator Research Organization

4) Graduate School of Engineering, Hokkaido University

5) Tokai Research Center, Japan Atomic Energy Agency


Boron Neutron Capture Therapy (BNCT) has been based on the thermal or epithermal neutron from the

research reactors. The neutron beam from the research reactors were optimized for the BNCT with high

neutron flux. This lead the clinical trial to various cancers such as malignant brain tumour, skin melanoma

and recently application to the head & neck cancer has been spread extensively. There are cancers of other

organs which may be indicated for BNCT (i.e., breast cancer, thyroid cancer, lung cancer, liver cancer,

chest wall cancer. etc.). However, by using research reactor for BNCT, the number of the patients is

limited and it could not be applied in the hospital where many medical equipment and medical staffs are

available.

With the recent advancement in accelerator technology, an interest of the neutron source for BNCT has

been increased and several practical projects for in-hospital accelerator based BNCT has been started.

The team of University of Tsukuba, High Energy Accelerator Research Organization, Hokkaido

University, Japan Atomic Energy Agency (JAEA) and private companies has created a project for LINAC

based BNCT treatment system. The accelerator technology was based on the previous R&D from the J-

PARC LINAC accelerator and it was modified for the special use for BNCT. The accelerator consists of

RFQ and DTL with beam energy of 8MeV and max. electrical current at 10mA.

The current status and the concept of the accelerator design will be presented and the optimum accelerator

capability for BNCT will be discussed.



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21. Japan-Tokyo, Itami

Conception and design of the first hospital-based BNCT facility

J. Itami1, Y. Abe

1, Y. Imahori

2, R. Fujii

2, M. Nakamura

2

1) Department of Radiation Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, 104-

0045 Tokyo, JAPAN

2) CICS, TOC Ariake Tower, Ariake 3-5-7, Koto-ku, 135-0063 Tokyo, JAPAN


In boron neutron capture therapy (BNCT), boron-10 accumulated in cancer cells experiences nuclear

reactions if irradiated with thermal neutrons. The resulting alpha and lithium particles with high LETs

sterilize cancer cells selectively. Up to now, the high intensity thermal/epithermal neutron beams only

were available at nuclear reactors. However, a reactor is not the optimal medical facility to treat

debilitated cancer patients and the transport of such patients to the reactor site is very demanding.

Consequently, the number of the patients that could be treated by BNCT remained limited and the clinical

results of BNCT could never reach an adequate statistical power. Recently, the development of accelerator

technology as well as suitable moderator design enables the introduction of accelerator-based BNCT in a

clinical environment. The National Cancer Center Hospital (NCCH) is preparing the installation of a

linear accelerator-based BNCT facility, which will be operational in 2014. A linear accelerator is installed

in floor B1 with proton acceleration up to 2.5 MeV with a beam courant of 20 mA. The proton beam is

bended 90° and to result a vertical beam from the top of the irradiation room, localized at floor B2. The

solid Li-target is layered over Cu + Pd with vacuum deposition to avoid blistering. The target is cooled

with a high efficient water chilling system to prevent melting of the target. The accumulated radioactive 7B in the target by

7Li (p, n)

7B is monthly cleansed by pure water and stored as radioactive waste in

reservoir tanks in a controlled area.

After characterization of physical and radiobiological properties of the resulting neutron beam, we intend

to start clinical trials in the second half of 2014. As boron carrier, 10

borono-phenylalanine (BPA) will be

used. For the evaluation of selective BPA accumulation in the tumour, 18

F-BPA PET/CT can be performed

and only tumours with tumour/blood 18

F-BPA ratio > 2.6 will be recruited to accelerator-based BNCT.

We are preparing clinical trial protocols for malignant melanoma, brain tumours, and head and neck

cancers. NCCH has the highest amount of newly diagnosed cancer patients in Japan and will be able to

perform prospective clinical trials with an adequate number of recruited patients to obtain a significant

statistical power to demonstrate the effectiveness of BNCT.



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61

22. Japan, Ono

Experience of BNCT by KUR and Start of Clinical BNCT Trial by Small Cyclotron Based

Neutron Generator in KURRI

Koji Ono1, Minoru Suzuki

1, Shin-ichiro Masunaga

1, Akira Maruhashi

1, Yoshinori Sakurai

1, Hiroki

Tanaka1, Ken Nakajima

1, Takami Sato

2, Tomoyuki Asano

3

1) Kyoto University Research Reactor Institute, Osaka, Japan

2) Sumitomo Heavy Industries, Ltd. Tokyo, Japan

3) Stella Pharma Corporation, Osaka, Japan

KURRI started clinical BNCT research in 1974, 6 years later the first clinical trial in Japan, by Prof. H.

Hatanaka. He gave an intra-operative BNCT to the patient of malignant glioma with BSH. But, clinical

outcome was not good probably due to an inadequate patient selection and rack of basic researches

including related technologies. No simulation of neutron or dose distribution in the brain and also no

method to immediately measure 10

B concentrations were available. KURRI stopped clinical research after

this treatment for 15 years. We restarted the research in 1989 firstly to treat malignant melanoma by using

BPA. After then, clinical BNCT research to malignant brain tumour was also started again. At present,

KURRI group has accumulated over 500 cases of BNCT, and new accelerator neutron irradiation system

for clinical BNCT has been developed and started clinical trial from last October. In this paper, we report

the present status of BNCT in KURRI and new accelerator.


Working Document

62

23. Poland, Gryzinski

Epithermal neutron source at Maria reactor

N. Golnik

1, M.A. Gryzinski

2

1) Institute of Metrology and Biomedical Engineering, Warsaw University of Technology, Św. Andrzeja

Boboli 8, 02-525 Warsaw, Poland

2) National Centre for Nuclear Research, Andrzeja Sołtana 7, 05-400 Otwock-Świerk Poland


BNCT research program started in Poland in 2001, in former Institute of Atomic Energy in Świerk (now

the Institute is included to National Centre for Nuclear Research). The underwater neutron line for BNCT

was mounted along the H2 horizontal beam tube of the research reactor MARIA in Świerk. At that time

the line consisted of two pneumatic caissons coupled with a pneumatic system for emptying/refilling. The

neutron spectrum of the beam contained mostly thermal neutrons, so a fission converter was designed at

the mouth of the channel, but never constructed. After six years in the reactor pool, one of the caissons

was broken. It was decided to remove both caissons and to replace them by one pipe coupled with the

same pneumatic system as before. A new concept of an underwater, in pool fission converter has been

elaborated and the line was constructed in 2010.

According to the new concept, the uranium converter is located in the reactor pool, near the front

of the H2 channel. Tubular design of the internal channel makes the construction resistant to mechanical

load. The converter consists of 99 densely packed fuel elements EK-10 with enrichment of 10%, placed in

the triangle lattice with the distance of 12 mm. All fuel elements were carefully re-attested with special

attention to leak tightness. There is a possibility to remove the converter and to replace it with an

aluminium dummy. It is also possible to mount the converter after turn by 180° around the vertical axis, in

order to equalize thermal and neutron loads. A measuring probe with two thermocouples measures the

temperature increase in the converter. The line was equipped with moderator-filter system made with

lithium fluoride; nickel, titanium, bismuth and B4C.

At present, the line is technically availability for use however there was no possibility to get

financing for the BNCT scientific program, so the converter never was irradiated in the reactor, in order to

avoid production of nuclear waste.

Monte-Carlo calculations showed that the total neutron flux density at the entrance to the

converter is of about 1013

n cm-2

s-1

and flux density of epithermal neutrons at the entrance to the

filter/moderator of the beam is of about 2•109 n cm

-2s

-1.



Working Document

63

24. Russian Federation, Golovkov

Neutron therapy for cancer patients using the U-120 Cyclotron

V.M. Golovkov1, V.A. Lisin

2, L.I. Musabaeva

2, O.V. Gribova

2, V.V. Velikaya

2, J.A. Startseva

2,

A.R. Wagner1

1) National Research Tomsk Polytechnic University, 30 Lenin av.,Tomsk, Russia, 634050

2) Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences, 12/1

Savinykh street, Tomsk, Russia, 634028


Neutron therapy is carried out in Tomsk since 1983 on the base of Polytechnic University U-120

cyclotron. A therapeutic fast neutron beam of average energy 6.3 MeV is generated under beryllium target

irradiation by 13.6 MeV deuteron beam. Neutron therapy is administered to patients with head and neck

cancer, lymph node metastases, locally advanced breast cancer and local recurrence. Neutron therapy

planning programs are based on the results of dosimetric and radiobiological studies. Preoperative neutron

therapy was given to 46 patients with cancer of the maxillary sinus and nasal cavity. The control group of

45 patients received the conventional photon therapy. The overall 5-year survival rates were: (62±9.6)%

(p<0.05) (in the neutron therapy group and (42±9.5)% in the control. The 5-year recurrence-free survival

rates were (68±8.2)% and (40±9.2)%. At a follow-up of 10 years, 11 of the 38 patients (29%) are still

alive in the neutron therapy group and none is alive in the control. For patients with parotid gland cancer

(n=52) postoperative neutron therapy provides: the 5- and 10-year relapse-free survival rate were

(72,4±9.8)% and (32,2 ±16,8)% versus the 5-year survival rate (25.6 ±19.1)% in control group. The 3- and

5-year survival rates were (60.6±13.6)% and (48.5±15.3)% after neutron therapy patients with salivary

gland cancer (n=22), compared to (30±16,9)% and 0% after photon therapy. Overall 5-year- and relapse-

free survival rates for patients with thyroid cancer (n=33) after postoperative neutron therapy were

(70.4±7)% and (72.4±9.8)% compared to 40% after combined neutron and photon therapy. Preoperative

neutron therapy was given to 100 patients with locally advanced breast cancer (T3-4N0-2M0) at a single

dose of 1.8-2.7 Gy up to a total dose of 7.2 Gy in combination with external radiotherapy delivered to the

areas of lymphatic spread and polychemotherapy. Local recurrence occurred in 2% of cases. The overall

8-year survival rate was (70.8±5.8)% versus (40.6±7.5)% in the control. The recurrence-free survival rate

was (96.0±3.0)% versus (57.9±7.4)% in the control. A new method for treatment breast cancer local

recurrence using fast neutrons and neutron + photon therapy have been developed. Overall 6-year survival

rate was (92.2±5.7)% (n=95) versus (51.5±9.1)% in the control group.



Working Document

64

25. Russian Federation, Lipengolts

Neutron Capture Therapy on Research Reactor of National Research Nuclear University

MEPhI. Facility, Preclinical Results, Future Prospects

A. A. Lipengolts1,2,3

, V.F. Khokhlov1, V.N. Kulakov

1, I.N. Sheino

1, A.A. Portnov

2, K.N. Zaitsev

2,

A.M. Arnopolskaya2,3

1) Burnasyan Federal Medical and Biophysical Centre, Russian Federation, 123182, Moscow, ul.

Zhivopisnaya, 46

2) National Research Nuclear University MEPhI, Russian Federation, 115409, Moscow, Kashirskoye sh.,

31

3) Blokhin Russian Cancer Scientific Centre, 115478, Moscow, Kashirskoye sh., 24


In 2004, the Research Reactor of the National Research Nuclear University MEPhI (former Moscow

Engineering and Physics Institute) with the rated power of 2.5 MW was equipped with a thermal neutron

beam for Neutron Capture Therapy (NCT) by reconstructing one of its horizontal neutron channels. The

obtained neutron beam has a flux of 6x108 n/cm

2s. Using this neutron beam, the NCT technology was

realized with the boron-containing drug boron-phenylalanine (BPA) and gadolinium-containing drug Gd-

DTPA. Over 60 dogs with spontaneous inoperable malignancies were treated with NCT. NCT with BPA

resulted in 80% full tumour regression and NCT with gadolinium and intra-tumoural drug administration -

in 46%. Also, an experiment of treating a dog with spontaneous osteosarcoma using BNCT with

extracorporeal bone irradiation and its re-implantation was performed. This experiment was highly

successful: full tumour regression was observed, and the total life span without recurrences was 2.5 years.

Currently, the thermal column of the reactor is being reconstructed to obtain an epithermal neutron beam

on another horizontal channel of the reactor. This new beam is planned to be used for clinical NCT studies

and trials.



Working Document

65

26. United Kingdom, Schütz

Boron Analysis and Boron Imaging in BNCT

Christian L. Schütz

1, Gabriele Hampel

2, Jens-Volker Kratz

2, Tobias L. Ross

2, Nicolas H. Bings

3,

Stuart Green4, Garth Cruickshank

1

1) Department of Neurosurgery, School of Cancer Sciences, The University of Birmingham, Queen

Elizabeth Hospital, Birmingham B15 2TH, United Kingdom

2) Institute of Nuclear Chemistry, University of Mainz, 55099 Mainz, Germany

3) Department of Inorganic and Analytical Chemistry, University of Mainz, 55099 Mainz, Germany

4) Department of Medical Physics, The University of Birmingham, Queen Elizabeth Hospital,

Birmingham B15 2TH, United Kingdom


Reliable boron analysis in biological samples is a key issue in BNCT. Each employed analytical technique

allows boron determination at a certain spatial resolution, which determines the biological relevance of the

data gained during analysis. Macroscopic analysis may offer information about rough boron distributions

in larger tissue compartments, like the mean boron concentration in a whole tumour. With increasing

resolution down to the cellular and subcellular level, it is possible to derive information on a microscopic

scale concerning cellular boron uptake, distribution, transport behaviour, and metabolism of the boron

carrier molecule. There is a significant difference between non-destructive and destructive analytical

techniques. For the latter, often only an integral (or bulk) determination of boron is possible, therefore, the

dimensions of a biopsy automatically present the limit of the resolution. Non-destructive methods

however may be not always applicable as they analyse only parts a sample, e.g., the surface, or because

they offer insufficient power of detection, like some radio-spectroscopic methods. Furthermore, if boron

analysis is required in vivo, a non-invasive method will be chosen. This is usually accomplished by radio-

analytical methods.

Boron analysis is crucial for both preclinical research and the clinical application of BNCT. During the

latter, boron analysis is needed to carry out the treatment itself, e.g., by monitoring the boron

concentration in blood during the infusion of the administered boron compound, to provide information

about the expected boron concentrations in tissue.

It is not the intention of this presentation to comprehensively review analytical methods, but rather to give

an overview of the most commonly methods used in BNCT. In this context, both instrumental and radio-

analytical methods with a brief summary of the corresponding analytical figures of merit and their

applicability in BNCT will be presented. Also, comparability, sample throughput and quality management

of the respective techniques will be discussed.



Working Document

66

27. USA, Kroc (video recorded)

Progress in Radiobiology Studies for Neutron Therapy

T. Kroc

Fermilab, PO Box 500, MS301, Batavia, Il 60510, USA


This presentation will describe work in radiobiology that has been conducted at Fermilab. A number of

studies have been conducted to investigate neutron capture therapy using both boron and gadolinium.

Doing so requires modifying the energy spectrum of the fast neutron beam.

One aspect of our work has is the accumulation of a database of cell death pathways for glioblastoma

multiforme cells when exposed to photons, fast neutrons, and our modified spectrum with gadolinium.

Simulation studies that support the design of the modified energy spectrum along with features and

consequences that arise will be described.



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67

28. USA, Fermilab, Welsh (not presented)

Proposed New Boron Neutron Capture Therapy Program at Fermilab-Program Overview

James S.Welsh1,2,3

, Hiren Patel2, Rahul Gupta

2, Thomas Kroc

1, Barrie P. Bode

3, Christine K.

Andorf1,Narayan S. Homane

2

1) Fermi National Accelerator Laboratory, P.O Box 500, Mail Box-301, Batavia, IL 60510

2) Dept. Of Chemistry and Biochemistry, Northern Illinois University, 1425 West Lincoln Highway,

Dekalb, IL 60115

3) Dept. Of Biological Sciences, Northern Illinois University, Dekalb, IL 60115


The Neutron Therapy Facility at Fermi National Accelerator Laboratory treated its first patient using

fast neutrons in September 1976. It continues to provide beam for therapy and radiobiology research.

A multidisciplinary team of radiation oncology, chemistry, biology and physics specialists along with

the availability of linac-generated fast and epithermal neutron beams, makes this a unique program

and an ideal environment to reinitiate investigations into BNCT and boron neutron capture enhanced

fast neutron therapy. The Fermilab p+(66)Be(49) fast neutron beam, which has a mean neutron energy

of 25 MeV, can be modified for the purposes of BNCT. The resultant moderated beam is enriched in

the epithermal energy range, making it potentially suitable for BNCT of deep-seated tumours. The

beam modifying assembly uses a tungsten filter and collimator with a graphite reflector to moderate

the fast neutrons down into the epithermal range. The assembly was designed based on Monte Carlo

radiation transport code MCNP version 5 for a standard 20x20 cm2

treatment beam. In parallel with

the physics advancements, our team has been developing and evaluating various new boronated

compounds (e.g. glutamine derivatives). These compounds utilize monosaccharides and glutamine,

two highly absorbed nutrients by cancer cells to transport boron across plasma membranes. Biological

evaluations suggest that these compounds offer improved bio-distributions over traditional BNCT

agents. Additionally, we propose addressing two primary malignancies in future clinical trials

(glioblastoma in humans and locally advanced bladder cancer in veterinary patients) if the final

analysis of the modified beam proves acceptable for clinical implementation.



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68

29. USA, Emery

University of Washington Medical Center Clinical Neutron Therapy System: Status Report

R. Emery1, G. Laramore

1, G. Sandison

1, R. Stewart

1, A. Kalet

1, G. Moffitt

2

1) Department of Radiation Oncology, University of Washington Medical Center,1959 NE Pacific St., Box

356043 Seattle, WA 98195-6043, U.S.A.

2) Nuclear Engineering Program, University of Utah,50 South Central Drive, Room 2234 MEB

Salt Lake City, UT 84112, U.S.A.


The University of Washington Medical Centre Clinical Neutron Therapy System, in its 29th year of

operation with close to 3000 patients treated, is one of two remaining fast neutron therapy facilities

treating patients in the US. The longevity of this program can be ascribed to commitment from physician

and faculty leadership, an exceptional maintenance program, and the fact that the system was designed

from the start for ease of modification to take advantage of advances in computer system technology and

with the flexibility to support research in a variety of areas including medical isotope production, boron

capture enhanced fast neutron therapy, and proton therapy. Present and future challenges for the facility

include Oncology Information System (OIS) integration, improved treatment planning, advanced imaging,

aging equipment, declining patient volumes, and requests for treatment prescriptions resembling photon

Intensity Modulated Radiation Therapy (IMRT).


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