4 Boron Neutron Capture Therapy • Glioblastoma: theinvasive nature makestreatment difficult.• BNCT has thepotential to selectivelytarget these infiltratingtumor cells.
5 The BNCT Reaction2.33 MeV of kinetic energy is released per neutron capture:initial LET ke V/µmLi-7 recoil ionMeV Gammathermal neutronAlpha particleThermal cross-section = 3837 barns (that’s very big…)
6 Boron Neutron Capture Therapy Selectively deliver 10B to the tumor.2. Irradiate the tumor region with low energy neutrons (nth).3. The short range of the 10B(n,α)7 Li reaction productsrestricts most of the dose to the boron-loaded cells.
7 BNCT Pre-History 1932: Chadwick discovers the neutron 1935: Taylor and Goldhaber describe the 10B(n,α)7Lireaction1936: Locher proposes BNCT as a cancer therapy1951: Brookhaven Graphite Research Reactor1951: W. Sweet, Chief of Neurosurgery at the MGHinitiates BNCT clinical trial
14 Failure of the First BNCT Trials • Poor penetration of thermal neutrons in tissue.• Boron levels in blood higher than those in tumor.• Viable tumor was found at depth following dosesthat exceeded the tolerance of normal surface tissues.• BNL and MIT clinical trials were stopped in 1961.
19 Photon-Equivalent Doses IAEA Workshop (6/99) recommends that BNCT doses beexpressed as a weighted dose Dw, with the unit Gy, using thefollowing convention:Currently:weighting factors termed RBE or CBE factors;BNCT doses expressed in Gy-Eq units
24 Dose response: ED50endpoint x raysthermal neutronsthermal neutrons+ BPA‧Compareisoeffectivedoses (ED50)Coderre et al., Radiat.Res., 152, 113, 1999
25 BNCT radiobiology Weighting Factors Used in Clinical Trial Tissues studied:Weighting Factors Usedin Clinical Trialtumorbrainspinal cordskinoral mucosa10B biological effectiveness factors range from 1.3 to over 5.An RBE of 3.2 is used for the high-LET beam components in alltissues.
26 Dog brain irradiations Dose volume histogramsIsodose contoursCoderre et al., J. Neuro-Oncol., 48, 27, 2000.
27 Dog brain irradiations Asymptomatic MRI changesMassive edema at 5 mos.6 mos.post-BNCTCoderre et al., J. Neuro-Oncol., 48, 27, 2000.
28 Dog brain irradiations ‧Average wholebrain dose, single-field irradiation.‧1 Gy = 1 joule/kg‧2 Gy = conventionaldaily fraction fortumors (x 30d).‧10 Gy whole body(brain) used in bonemarrow transplant.fast neutronsnitrogengammaboronAverage Brain Dose (cGy or cGy-Eq)Dog 1655:Lethal necrosisin 5 monthsDog 3746:No changesin 3 years
29 The BNCT procedure Surgery 3-4 weeks prior to BNCT. BNCT is given in a single sessionlasting less than 1 hr.• 2-hr BPA infusion• BNCT starts ~ 45 minafter end of infusionCoderre, et al., J. Neuro-Oncol., 33, 141, 1997.
30 Monte Carlo-based treatment planning TumorTarget volume(tumor + 2 cm)
31 Brain • One field versus two fields • Peak dose, hemisphere dose, whole brain average dose
32 MITR-II showing current and new epithermal beam locations
33 Brain Doses BNL BNCT clinical trial. Reference (peak) doses in brain (maximum doseto a 1 cm3volume).Doses escalated in 20%increments.Reference Dose (Gy-Eq)ProtocolChanana, et al., Neurosurg., 44, 1182, 1999.
34 Brain Doses BNL BNCT clinical trial: Whole-brain average doses. CNS side effectsobserved in 2 pts inProtocol 4b and all pts inProtocol 5.Dose (Gy-Eq)Protocol
35 Brain: Dose Volume Histograms for the Normal Brain• Escalation of the dosein humans.• Comparison to themaximum tolerated dosein dogs.Fraction of Volume (%)Effective Dose (Gy-Eq)
36 Normal Brain Tolerance fieldsfieldsfieldDose (Gy-Eq)
37 Normal Brain Tolerance BNL Patientswith Somnolence% Brain VolumefieldsDose(Gy(w))
39 Normal Brain Tolerance BNLBNL with somnolenceMITMIT with somnolencePeak Dose (Gy(W))Whole-Brain Average Dose (Gy(W))
40 Normal Brain Tolerance somnolence probability (%)Average Brain DosePeak Brain Dose5% confidenceDose (Gy(W))
41 Patient survival data alive alive with recurrence deceased 1 -4a = single field4b = two fields5 = three fieldsSurvival Post-Diagnosis (months)Approximate median survivalwith standard therapy(Curran, JNCI, 85, 704, 1993)Status as of 5/03BNCT Protocol number
42 Patient survival data BNL BNCT Data - All Patients Probability of SurvivalTime post-diagnosis (months)
43 Clinical Trial Summary • Escalation of neutron exposure may havereached CNS tolerance limits• The BPA-F dose has only been marginallyescalated so far.• No tumor dose-response has been observed.
44 Tumor Doses Minimum dose to the contrast- enhancing tumor volume. • CalculatedGy-Eqdoses arevery high: 40, 50, 60Gy-Eqin asingle-fraction.• Tumor recurrence has beenlocal in the majority of cases.• Tumor necrosis has beendocumentedhistologically.Dose (Gy-Eq)Protocol
45 Tumor: Questions • Does surgery affect BPA uptake in tumor? • Do all tumor cells take up boron?• Do infiltrating tumor cells accumulateboron as well as the main tumor mass?
49 Improve BPA delivery to tumor • Rat 9L gliosarcoma• Infiltrating tumor cellstake hours to reach thesame BPA level as themain tumor mass.[10B] MTM / [10B] clustersIon microscopy at Cornell Univ.; D.Smith G. Morrison.Time of infusion (hrs)Smith et al., Cancer Res., 22, 8179, 2001
50 Clinical trial in Studsvik 6-hrBPAInfusion:900 mg/kg10B concentration (ppm)WB avedose3-6 Gy-EqJNO, 62, 135, 2003Time from start of Infusion (hrs)
51 BNCT Patient Survival Studsvik: 6-hour BPA infusion Harvard-MITBNLStudsvikStudsvik:6-hourBPAinfusionProbability of SurvivalJNO, 62, 135,2003Time after Diagnosis (Months)
52 Currently… • BNCT clinical trial for GBM in Sweden evaluating 6-hour BPA infusions.• MIT clinical trials now open:• Two BNCT fractions on consecutive days• GBM or melanoma metastatic to the brain• Cutaneous melanoma.•Other BNCT clinical trials underway in Finland, Japan,The Netherlands, Czech Republic.
53 Clinical Trials: New Directions Other SitesHead and NeckBrain Metastases (multiple)Lung?Criteriapoor local controlsensitive normal tissues limit dosecurrent therapies not effective
54 Clinical Trials: New Directions Retreatment: BNCT for recurrent GBMCombinationsBPA + another boron compound(GB-10, BSH, CuTCPH, BOPP)BPA + radiosensitizerGd-texaphyrinBPA + photonswhole brain photonsradiosurgery