Ravishanker Final BNCT report.pdf - University of Surrey

NEUTRON ACTIVATED BORON THERAPY FOR CANCERTREATEMENTbyRAVISHANKER LINGOTPAVANATHARA dissertation submitted to the Department of Physics,University of Surrey, in partial fulfilment of the degree ofMaster of Science in Radiation Detection and InstrumentationDepartment of PhysicsFaculty of Engineering and Physical SciencesUniversity of SurreyAugust 2010© L.RAVISHANKER 2010

University of surreyAcknowledgementsI would like to thank my supervisor professor Paddy Regan for all his guidance and advisethrough this project.In addition I want to thank all the staff and students that have been tremendously helpful andgiven me a lot of support.Finally I would like to thank my family for their encouragement love and support, especiallyfor my mom for her financial support.L.Ravishanker II

University of surreyTable of ContentsChapter 1 11.1 What is BNCT? 11.2 What is the requirement for a BNCT? 21.3 Monte carlo 21.4 The treatment planning 2Chapter 2 32.1 Design of BNCT 32.2 Boron delivery agent 42.3 Neutron beam 4Chapter 3 73.1 The role of Radiobiology in BNCT 73.2 Beam contamination components. 73.3 Which factors affecting Radio biological effect? 73.4Role of chemistry in BNCT 83.5Cost impact 8Chapter 4 94.1 Radiation therapy in cancer treatment 94.2 Application of BNCT in cancer treatment 104.3 What tumors are suitable for BNCT 104.4 Comparison between BNCT and traditional radiotherapy 134.5 Discussion and conclusion 14References 15L.Ravishanker III

University of surreyAbstractBoron neutron capture therapy is very innovative cancer therapy. BNCT has undergonedramatic developments since its inception in 1936 by Locher. It is a complement for otherradiation therapy. In BNCT tumor seeking boron and epithermal neutron reaction producehigh linear energy alpha particle and recoil Li nuclei. They have destructive power and theycan only travel very short distance. The effect of BNCT depend on a sufficient cellular uptakeof boron followed by an exposure to epithermal neutron beam from a nuclear reactor.Currently many countries all over the world doing their clinical trails about BNCT. The outcome of their trail should be use full to improve the limitation of boron delivery agent andneutron beam. If they find a solution for the limitation then BNCT could move forward as atreatment modality.L.Ravishanker IV

University of surreyChapter 11.1 What is BNCT?Just 4 years after the discovery of neutron the concept of neutron capture theory wasintroduced in 1936 by G.L.Locher in Pennsylvania. (1, 2, 3) NCT is a promising method forcancer treatment where the conventional radiotherapy fail in some situation, the tumor hasnot well defined limit. Boron and Neutron constitute together a binary weapon against cancertheraphy. BNCT is a technique, very innovative cancer therapy and an investigational formof radiation therapy. That is currently in the development stage for the treatment ofgliblastoma mutiforme or anaplastic astrocytoma and all the form of human brain tumor. (4)Clinical trial of BNCT was started in 1951 by Farr et al and it was improved by sweet et al(5) . But the result of the clinical trials disappointing due to inadequate boron compounds. So itis discontinued in 1961 and further clinical trials were performed in 1968 by H.Hatanaka injapan and the results shows some outstanding agreement. (6) Then united state and someEuropean countries restarted their clinical trials about BNCT after the interesting andoutstanding outcome from the H.Hantanaka and co-works study. The International societyfor Neutron capture theraphy was founded in 1984 after the encouraging out come from hisclinical trials (19) . Before start of clinical trials, The development and construction of BNCTfacility were realised at LVR reactor of NRI for treatment of human brain gliomas. (2)Boron neutrons capture therapy based on two phenomena. First one, Non radioactive boronDrag was delivered through injection to the tumor tissue and the next one, patient wasirradiated with epithermal neutron until the normal tissue dose limit is reached. Theadvantage of the boron is it has large cross section (3840 barn) for slow thermal neutron. (2,3)10B + 1n → 7Li + 4HeFigure 1.1: Nuclear reaction utilized in Boron neutron capture therapy. (7)L.Ravishanker 1

University of surreyWhen thermalised neutron captured by the non radioactive boron atom, it decays throughshort range α-particle and recoiling Li-7 nucleus. These emitted charged particles can travelonly a short distance (10µm) (8, 20) , have a high linear energy transfer and an associated highrelative biological effectiveness. This energy has an ability to locally destroy the cancertissue that containing the boron drag without appreciably harming the healthy cell around thetumor cell. (6)1.2 What is the requirement for a BNCT?In this study of BNCT some sort of parameters should be considered during this researchperiod.1. Boron concentrationIt is necessary to keep a large number of B-10 atoms localized selectively within thetumor cell.2. Neutron beamOn the other hand a sufficient number of neutrons must reach and captured by theboron atom.1.3 Monte carloIt is used to solve the complex mathematical equation. In radiation physics it is use to solvethe Boltzmann transport equation to tracks individual particles from the source.1.4 The treatment planningSome of the technical things are considered in treatment planning are generate a fixedneutron source in reactor, optimize the beam quality & provide a plane source for patientdose evaluation and the final one is calculate the dose distribution and performed thetreatment planning. (21)The radiation geometry.The number of irradiation field.The quality of the irradiation fields.The duration of the irradiation.A treatment planning is scheduled and does through the following phases. First the patient isscanned with CT or MRI scanning. Monte carlo simulations and the region of interest arecalculated by using the CT and MRI scanning medical images. Dose calculation and thepositioning of the irradiation fields are made by using the monte carlo result. Then the patientis positioned in the irradiation room and the pre calculated irradiation beam is applied to thepatient. Beam monitoring is very important to control the patient exposures and maintain thestability of the neytron beam during the irradiation. (21)L.Ravishanker 2

University of surreyChapter 2In this chapter the quality of the boron compounds and optimization of the delivery, and theirradiation technique were briefly analyzed and the essential for accelerated based epithermalneutron for BNCT.2.1 Design of BNCTThe neutron beam’s intensity and quality are the main factors in the treatment of brain tumorby BNCT. Currently there are three types of neutron sources widely use in medical field.Those are radioactive isotope, Fission reactor and Accelerator. (22) It is strongly recognisedthat epithermal neutrons are suitable than the thermal neutron. Earlier they use reactors toproduce neutron beam for BNCT but it can only produce the thermal neutron, so increase itability now a days they are interest to use accelerators to produce epithermal neutron. (8)Figure 2.1: Block diagram of BNCT (9)Figure 2.1 describes the block diagram of the treatment of cancer by BNCT and how it iscontrol and monitor in hospitals.L.Ravishanker 3

University of surrey2.2 Boron delivery agentThe success of the BNCT mainly depends on the boron delivery agent. The major challengein the development of boron delivery agents has been the requirement for selective tumortargeting to achieve boron concentration (~20mg/g tumor) sufficient to deliver therapeuticdoses of radiation to the tumor with minimal normal healthy tissue. (10)A polyhedral Borane Anions and carbonates compound is very effective for BNCT whichhave an advantage of facilitating a higher concentration of boron absorption into tumors. (k)Types of Boron compounds using in BNCT Borocaptate sodium (BSH) Para-boronophenylalanine (BPA)Figure 2.2 chemical structures of BPA and BSH compounds.2.3 Neutron beam(11, 12)One of the major problems raised by the BNCT technique is to obtain a suitable beam ofneutrons in terms of intensity and energy spectrum. The neutron flux must meet severalrequirements simultaneously. But the neutron beam requirements peculiar to the BNCTmethodology are complex and difficult to achieve in practice. The preferred characteristics ofthe neutron beam are given below1. It should kept High thermal neutron flux intensity at the tumor cell for reducingirradiation time. The epithermal neutron flux nearly 10 9 neutron/ cm 2 sec. (1,2)2. Neutron energy is from 1eV to 10keV3. The second one is Low high energy neutron component for sparing the healthy tissue.L.Ravishanker 4

University of surreyNeutrons are classified three types according its energy as thermal neutron (energy 10keV). (13, 18) Athermal neutron beam can be very effective for the treatment of tumors because it has largecross section for Boron Neutron capture reaction.Reactors are the most suitable type for neutron source because of it provides correct energyspectrum and adequate thermal high intensity neutron flux. Unfortunately the experimentalnuclear reactors are not close to the hospital because of its size. (z8)The new idea of the small reactors is not attractive for BNCT due to its low acceptability ofsuch structure inside a hospital atmosphere and the high investment cost. That’s why a verityof accelerator based neutron source proposed and investigate now. Theoreticallyradiofrequency Quadra pole (RFQ) accelerators have capacity to use as a neutron source inBNCT. (2) To get an appropriate neutron source modelling of neutron from the target is veryimportant. Monte carlo program is used to moderate and filter the neutron beam. In the worldthe first clinical based dynamitron accelerator facility is built at the University ofBirmingham. (13) Accelerators can produce epithermal neutron.Figure 2.3: comparison of flux depth distribution in phantom for thermal and epithermalneutron. (2)Neutron sources providing an epithermal spectrum ranging from 0.4 eV to 10 keV are beingconsidered for clinical use for the treatment of deep-seated tumours such as gliomas.L.Ravishanker 5

University of surreyChapter 3The BNCT group of specialists from different scientific fields such as physics, medicine,chemistry, radiobiology, etc acquired a great experience in the course of this long timeactivity. (25)3.1 The role of Radiobiology in BNCTThe role of radiobiology in BNCT is very complicated than the other traditionalradiotherapies.3.2 Beam contamination components.In the treatment of BNCT the radiation dose to the patient is consists of three maincomponents.• Neutron doseo This component is subdivided in to the dose component due to the fast,epithermal and thermal neutron. The fast neutrons have some undesirablecharacteristics. So in the design of BNCT made to reduce the fast neutroncomponent in the incident beam. To increase the effectiveness of the BNCT itis necessary to have a high epithermal flux (2.5 to 13 x10 -13 Gy cm 2 ) (2)• Gamma doseo This dose component affects both tumor and healthy tissue to the same degreeand it should be reducing the effectiveness of the cancer treatment. But we canreduce this component by doing some careful beam design. Bi and Pb isplaced in the beam to block the gamma ray in the incident beam and theadvantage of those materials are transparent for neutron beam.• Boron doseo This is due to the high linear energy transfer heavy charged particle from theproduct of the fission reaction of boron-10, we have to keep the boron dose inthe tumor tissue should be high and low in the surrounding normal tissue.3.3 Which factors affecting Radio biological effect?Relative Biological EffectivenessThis is the ratio of the absorbed dose of the reference source of a radiation to that of the testradiation that produced in the same biological effect. It is only applicable for homogeneousdistributions. To find the efficiency of the BNCT, calculation of dose distribution of tumor tonormal tissue is very important.L.Ravishanker 7

University of surreyCompound Biological EffectivenessIn the injection of boron drug for tumor cell is inhomogeneous, so RBE is not applicable inthis criteria. In this situation we calculate the compound biological effectiveness that isdefined as the product of the RBE and the boron distribution.3.4 Role of chemistry in BNCTBoron is a group 4 element in the periodic table which has a complex chemistry comparedwith other elements. Boron has two naturally occurring isotrope 10 B and 11 B. In BNCT 10Bis used commenly because of the non radioactive ability. Carboranes are very good source ofmultiple boron atoms and it is used in a lot of application of medicine. (23)3.5Cost impactCost of accelerators, the building and medical equipment are the factors take a main role inthe cost impact. Maintenance of the equipment, medical materials, and personal salaries arethe other components.Figure 3.1 BNCT cost analysis report. (16)L.Ravishanker 8

University of surreyChapter 44.1 Radiation therapy in cancer treatmentCancer is a kind of diseases in which abnormal cells divide uncontrollably. Every daythousands of people are diagonised with cancer. The treatment of diseases with ionizingradiation is defined as the radiotherapy. Radiation is an efficient and safe for all kind ofpatients.Radiation treatment was used for cancer treatment from the early part of nineteen century.After that it is improved for deliver higher dose to the tumor other than the healthy tissue byusing multiple fan beams, optimizes treatment planning and shielding. There are two type of(2, 24)radiation is common now a days. Those are described below External Beam radiotherapy (teletherapy)o In this cancer treatment the source of the radiation is keep out side the patient.Mast of the deep seated tumors can treat by this method. Compare to othercancer treatments this is very cheep and the maintenance cost also lower thanothers. But the disadvantage of radiation treatement include prolong treatmentand associated toxicity in some patients. Brachytheraphyo In this brachytherapy the radiation drug is implanted into the tumor area byinjection. Patients do not fell any pain during this treatment. In this methodthat is easy to give high dose in the tumor within shorted time and the healthytissues also sparing from the radiation.In both methods there is a possibility to occur side effects because the radiation causesdamages to the healthy organs surrounded to the tumor tissues.What types of cancers typically treated now?‣ Tumors in brain and spinal chord‣ Lung cancer‣ Head & neck cancer‣ Eye cancer‣ Prostate cancerL.Ravishanker 9

University of surrey‣ Lymphoma‣ Pediatric tumors‣ Breast‣ skinConventional cancer treatments failed to selectively preserve healthy tissue and eradicate allmalignant cells. To cover this crucial problem the concept of BNCT introduced and it seemsto have good prospects.4.2 Application of BNCT in cancer treatmentSince BNCT is a biologically rather than physically targeted type of radiation treatment. Intheory BNCT provides a way to deliver curative dose to the tumor while sparing normalhealthy tissue. The main advantage is it can treat apparent and undetectable tumors.4.3 What tumors are suitable for BNCT The tumor should have accessible to beam delivery The tumor has an ability to take up boronated drus.Currently some type of tumors in brain, recurrent head & neck, colon mets in liver andmelanoma are treated by BNCT with successful evidence. Glioblastoma was the first tumortreated by BNCT in 1999 at Finnish Research reactor. (17) In the case report some of theefficient BNCT treatments are mentioned.Figurer 4.1: Clinical successful BNCT treatment report(13, 18)L.Ravishanker 10

University of surreyCase reports‣ A subject was a fifty year old man who had speech problem and right hemi paresis.Doctors found that there was a tumor stain in his left front parietal area. In June of1972 he treated by BNCT and 11 years after he checked by CT scan. It showed thatno recurrence of the tumor. The man was still in healthy and doing his farming in hisage of 70. Figure 4.2 show the CT image of the person. (5)Figure 4.2: radiation planning (left) and right picture CT image, 15years after the BNCT‣ Second case study is a sixty year old woman had tumor of glioblastoma. In July 1977she was under treated by BNCT and 16 years after MRI scanning, illustrated in figure4.3 showed that there was no recurrence of the tumor. (5)Figure 4.3: MRI image, 16 years after the BNCT treatement.L.Ravishanker 11

University of surrey‣ An eleven years old girl with tumor in her right frontal lobe. She was underwentBNCT in October 1981. In 1994 MRI studied show that there was no recurrence ofthe tumor. Images are illustrated below figure 4.4. (5)Figure 4.4 radiation planning and right figure 13 years after the BNCT‣ A subject was a woman in her age of 41 who suffered from headache, tested by MRIscan; it showed an enhanced mass in the left parietal. In 1992 the BNCT wasperformed and after the treatment the MRI studied images in figure 4.5 show thatmarked decrease of the enhanced lesion. (5)Figure 4.5: Radiation planning second fighre follow up MRI 3 years after the BNCTL.Ravishanker 12

University of surrey‣ A woman in her age of 54, suffered from her fifth finger of right foot amputated onNovember 1999. Medical scanning demonstrated that she had a skin melanoma andshe was treated in October 2003.This skin melanoma successfully performed. (8.7)(Z13)In all kind of radiation treatment including BNCT should be face a risk of damage to healthyorgans. But compare to other treatment BNCT has less damaging than the otherconventional treatments.4.4 Comparison between BNCT and traditional radiotherapyAn ideal therapy for cancer is defined as to selectively destroy the tumor cells simultaneouslywithout affect the healthy normal tissues. Traditional radiotherapy use to treat the tumor byusing high energy X-ray or electron beams. (2) It has low linear energy transfer. In somesituation conventional radiotherapy fail to treat the tumors especially brain tumor. BNCT is agood complement of other form of therapy to destroy not only the apparent but also theundetectable tumors. In the development of BNCT, chemistry play a role to produce aeffective boron drug, biology play a role to determine if compound is preferentially taken upinto target cell, physics try to modelling neutron transport and determination of doseconcentration in the tumor and the whole body and engineering play a role in target design.Compare to the other heavy ion or photon therapies, BNCT is more cost effective thanothers.L.Ravishanker 13

University of surrey4.5 Discussion and conclusionThe conventional radiotherapy failed in some treatment of cancer like brain tumors. Not onlythe tumor tissues but the healthy tissues also destroyed by this radiotherapy. So researcherstry a new technique that is called as Boron neutron capture therapy just after the discovery ofneutron. The concept of BNCT is simple and elegant. BNCT have a potential to provide away to apply dose to tumor tissue which is mixed with the healthy tissue.The boron neutron capture reaction is unique and its potential applications to medicine are asimportant today as they were fifty years ago. The product particles from the neutron boroncapture reaction are α particle and the recoil lithium nuclei have high energy but thepenetration range is very small.Particle accelerator is a good choice to provide neutron source for this boron neutron capturereaction. Scientist tries to characterise the dose components and biological effects in eachcomponent of the tissues separately. The biological effectiveness is also high in the BNCT. Ithas the ability to destroy the malignant cells at high boron concentration than the normalhealthy cells.First clinical trial was conducted at the Brookhaven medical reactor and Massachusetts inthe period of 1950 to 1960. Unfortunately the result was not effective to demonstrate anyevidence for cancer treatment. The main reason is the low Boron concentration in the tumortissue. In 1968 Dr. Hatanaka and Dr. Sweet tried to improve the boron drag to develop theBNCT. During their study they got some attractive evidence to prove the therapeuticeffectiveness. All over the world research people inspired by his achievements andrecognized BNCT of its good performance on the therapeutic effect.High grade Gliomas, Glioblastoma and Melanoma are still resistance to form of radiotherapyincluding surgery chemotherapy immunotherapy and gene therapy. But BNCT is veryeffective and attractive method for curing malignant tumors, well tolerated technique formanaging recurrent gliomas.The clinical evidences show that BNCT is a new option for managing recurrent head andneck tumors. Throughout the clinical trials, BNCT is a promising technique for someparticular cancer treatment which appears to be able to safely and effectively treat advancedand otherwise untreatable tumors.The current study about BNCT is trying to improve the ability of the tumor targeting borondelivery agent and the development of the in-hospital accelerator base neutron beam withenough energy to penetrate the target organ with little face neutron contamination to increasethe effectiveness. These are the main limitation of the treatment. If they find a solution forthis limitation, then that should offer the effective outcome and BNCT could move forwardas a treatment modality.L.Ravishanker 14

University of surreyReferences1. M. Frederic Hawthorne and Mark W Lee A clinical assessment of Boron targetcompounds for Boron neutron capture therapy Journal of neutron-Oncology: 62 pageno: 33-45 20032. International atomic energy agency Current status of Neutron capture therapy may20013. Amos Breskin Studies of gamma-blind fast neutron imaging detector for BNCTapplication Anno accademico 2006-20074. Katariina Kortelainen Radiographers in BNCT treatement in Finland5. Y. Nakagawa Clinical practices in BNCT to the brain6. Teruyoshi Kageji Histopathological findings in autopsied glioblastoma patientstreated by mixed neutron beam BNCT Journal of neutro Oncology : 68 page number25-32 20047. www.nanomed.missouri.edu/researchpapers8. Grzegorz Tracz et al Nemerical optimisation of the fission-converter andfilter/moderator arrangement for the Boron neutron capture therapy Nukleonika :48page number 177-185 20039. www.jaea.go.jp/english/news/p06071001/index.shtml10. Minoru Suzuki First attempt of BNCT for Hetocellular carcinoma Jpn j clin oncol :37page number 376-381 200711. Chia Hung Hsieh et al Evaluation of pharmacokinetics of 4-borono-2-18F-fluro-Lphenylalaninefor Boron neutron capture therapy in a glioma bearing rat model withhyperosmolar blood brain barrier disruption J Nucl med :46 page number 1858-1865200512. www.myoops.org/twocw/nr/rdonlyres/22.../bnct_lect_s04.pdf13. Stuart Green Boron Neutron capture therapy march 200614. Heikki Joensuu Boron neutron capture therapy of brain tumors: clinical trials atFinnish facility using boronphenylalanine15. Hong Ming Liu MCNP code used for neutron beam design in BNCT Nuclear Scienceand Technical Development center 200616. Y.Nakagawa, H Yoshihara et al Cost analysis of radiotherapy Carbon ion therapyproton therapy and BNCT in Japan Applied Radition and isotropes :67 200917. Heikki joensuu.et.al BNCT of brain tumors, clinical. Trials at the finish facility.Using borono pheny lalanine18. Stuart Green. Binary therapies in the treatment of cancer. STFC innovations.Birmingham. 2010 January.19. Barry J. Allen Internal high linear energy transfer (LET) targeted radio theraphy forcancer. Phys.Med.Biol.51 (2006) 327-341.20. A.Valda . et al, A.J.Kreiner. Development of a tomographic system for online Dosemeasurement in BNCT. Brazilian Journal of Physics, Vol 35 No 313 , 2005.21. G.G.Daquino Treatment planning system for BNCT : Requirements and peculiarities.CERN-Open-2003-052.22. B.A.Ludewigt.et.al Clinical requirements and accelerator concepts for BNCT.IEE.E.,1998.23. Richard L.Julius,ct.al Synthesis and evaluation of transthy retin amyloidosisinhibitors containing carborane pharmacophores 2007.24. G.K.Rath Radiation theraphy in the measurement of cancer.25. G.G.Daquino,N.Cerullo. et.al BDTPS: The BNCT Treatement planning system jointlydeveloped at DIMNP & JRC/IE cern-opan 2003-051.L.Ravishanker 15