Dosimetry and dose planning in boron neutron capture therapy : Monte Carlo studies

Boron neutron capture therapy (BNCT) is a biologically targeted radiotherapy modality. So far, 249 cancer patients have received BNCT at the Finnish Research Reactor 1 (FiR1) in Finland. The effectiveness and safety of radiotherapy are dependent on the radiation dose delivered to the tumor and healthy tissues, and on the accuracy of the doses. At FiR 1, patient dose calculations are performed with the Monte Carlo (MC) based SERA treatment planning system. Initially, BNCT was applied to head and neck cancer, brain tumors, and malignant melanoma. To evaluate the applicability of the new target tumors for BNCT, calculation dosimetry studies are needed. So far, clinical BNCT has been performed with the neutrons from a nuclear reactor, while an accelerator based neutron sources applicable for hospital operation would be preferable. In this thesis, BNCT patient dose calculation practice in Finland was evaluated against reference calculations and experimental data in several cases. The suitability of the deuterium-deuterium (D-D) and deuterium-tritium (D-T) fusion reaction based compact neutron sources for BNCT were evaluated. In addition, feasibility of BNCT for noninvasive liver tumor treatments was examined. The deviation between SERA and the reference calculations was within 4% for the boron, nitrogen, and photon dose components elsewhere, except on the phantom or skin surface. These dose components produce 99% of the tumor dose and more than 90% of the healthy tissue dose at points of relevance for treatment at the FiR 1 facility. The reduced voxel cell size in the SERA edit mesh improves calculation accuracy on the surface. The erratic biased fast-neutron run option in SERA led to significant underestimation (up to 30 60%) of the fast-neutron dose, while more accurate fast-neutron dose calculations without the biased option are too time-consuming for clinical practice. Large (over 5%) deviation was found between the measured and calculated photon doses, which produces from 25% up to 50% or more of the healthy tissue dose at certain depths. The MC code version MCNP5 is applicable for ionization chamber response within an accuracy of 2% 1%, which is sufficient for BNCT. The fusion-based neutron generators are applicable for BNCT treatments, if yields of over 1013 neutrons per second could be obtained. The simulations indicate that noninvasive liver BNCT with epithermal neutron beams can deliver high tumor dose (about 70 weighted Gy units) into the shallow depths of the liver, while tumor doses at the deepest parts of the organ remains low (approximately 10 weighted Gy units), if the accumulation of boron in the tumor compared with that in the healthy liver is sixfold or less. The patient dose calculation practice is safe and accurate against reference methods for the major dose components induced by thermal neutrons. Final verification of the fast neutron and photon dose calculation is restricted to high levels of uncertainty in existing measurement methods.Boorineutronisädehoito (BNCT-hoito) on biologisesti kohdennettu sädehoitomuoto, joka perustuu booriatomien ja neutronien väliseen vuorovaikutukseen ja boorin kertymiseen kasvaimeen enemmän kuin terveeseen kudokseen. Tähän mennessä BNCT-hoidoilla on hoidettu 249 syöpäpotilasta Suomessa. Hoidot on toteutettu Suomen ensimmäisellä koereaktorilla (FiR 1), joka otettiin käyttöön vuonna 1962. Sädehoidon teho ja turvallisuus riippuvat kasvaimen ja terveen kudoksen saamasta säteilyannoksesta ja annoksen määrityksen tarkkuudesta. Suomessa BNCT- hoidoissa potilasannoslaskenta on toteutettu Monte Carlo -simulointimenetelmään perustuvalla SERA-annossuunnitteluohjelmalla. BNCT:tä on käytetty pään ja kaulan alueen kasvainten, aivokasvainten ja melanoomaan hoitona. Annoslaskentatutkimuksia tarvitaan selvittämään BNCT-hoidon soveltuvuutta uusien kohteiden hoitoon. Toistaiseksi BNCT on annettu neutroneilla, jotka tuotetaan ydinreaktoreissa, mutta hiukkaskiihdyttimet olisivat käytännöllisempiä neuronilähteitä, koska soveltuisivat sairaalaympäristöön. Tässä väitöskirjassa on verrattu erilaisia laskennallisia ja kokeellisia menetelmiä BNCT-annosmäärityksessä. Lisäksi on tutkittu laskennallisesti deuterium-deuterium (D-D) ja deuterium-tritium (D-T) fuusioon perustuvien neutronilähteiden soveltuvuutta BNCT-hoitoon, ja selvitetty onko saavutettavan annosjakauman puolesta mahdollista hoitaa maksakasvaimia ulkoisella BNCT:llä. SERA-ohjelmalla ja verrokkimenetelmillä laskettujen boori-, typpi-, ja fotoniannosten ero on korkeintaan 4 %, jos pinta-annosta ei oteta huomioon. Nämä annoskomponentit muodostavat 99 % kasvaimen annoksesta ja yli 90 % terveen kudoksen annoksesta hoidon kannalta merkittävillä syvyyksillä. Pinta-annoksen laskentatarkkuus paranee, kun SERA-ohjelman laskentahilan kokoa pienennetään. Erillinen nopeiden neutronien aiheuttaman annoksen laskentamalli SERA-ohjelmassa ei ole riittävän tarkka ja se aliarvioi nopeaneutroniannoksen jopa 30−60 %, mutta ilman erillistä mallia nopeiden neutronien annoksen laskeminen riittävällä tarkkuudella on liian hidasta käytännön potilastyössä. Suuri ero löydettiin myös lasketussa ja mitatussa fotoniannoksessa, joka aiheuttaa vähintään 25 %, mutta jopa 50 % terveen kudoksen annoksesta tietyillä syvyyksillä. Tulosten perusteella Monte Carlo -ohjelma MCNP5 soveltuu fotonimittauksissa käytetyn ionisaatiokammion vasteen mallintamiseen 2 % tarkkuudella, joka on riittävä BNCT:ssä ja mahdollisesti tulee parantamaan fotoniannoksen määrityksen tarkkuutta. D-D ja D-T fuusioneutronilähteet soveltuvat BNCT -hoitoihin, jos tuottavat yli 1013 neutronia sekunnissa. Epitermisillä neutroneilla annettu maksan ulkoinen BNCT -hoito aiheuttaa pinnallisiin kasvaimiin jopa 70 painotetun grayn sädeannoksen, mutta syvällä maksassa sijaitsevien kasvainten annos jää pieneksi (noin 10 painotettua grayta), jos kasvaimen booripitoisuus on enintään kuusinkertainen verrattuna terveen maksakudoksen booripitoisuuteen. Tärkeimpien, termisten neutronien synnyttämien, annoskomponenttien laskenta SERA-ohjelmalla on todettu tarkaksi verrokkimenetelmiin verrattuna. Nopeiden neutronien ja fotonien synnyttämän säteilyannoksen varmistamista rajoittaa mittausmenetelmien epätarkkuus. Käytössä oleva potilasannoslaskentamenetelmä on turvallinen ja tarkkuudeltaan hyvä

Effect of the Calibration in Water and the Build-up Cap on the Mg(Ar) Ionization Chamber Measurements

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Boron neutron capture therapy for locally recurrent head and neck squamous cell carcinoma : An analysis of dose response and survival

Background and purpose: Head and neck squamous cell carcinoma (HNSCC) that recurs locally is a therapeutic challenge. We investigated the efficacy of boron neutron capture therapy (BNCT) in the treatment of such patients and the factors associated with treatment response and survival. Methods and materials: Seventy-nine patients with inoperable, locally recurred HNSCC were treated with L-boronophenylalanine-mediated BNCT in Espoo, Finland, between February, 2003 and January, 2012. Prior treatments consisted of surgery and conventionally fractionated radiotherapy to a median cumulative dose of 66 Gy (interquartile range [IQR], 59-70 Gy) administered with or without concomitant chemotherapy. Tumor response was assessed using the RECISTv. 1.0 criteria. Results: Forty patients received BNCT once (on 1 day), and 39 twice. The median time between the 2 treatments was 6 weeks. Forty-seven (68%; 95% confidence interval [CI], 57-79%) of the 69 evaluable patients responded; 25 (36%) had a complete response, 22 (32%) a partial response, 17 (25%) a stable disease lasting for a median of 4.2 months, and 5 (7%) progressed. The patients treated with BNCT twice responded more often than those treated once. The median follow-up time after BNCT was 7.8 years. The 2-year locoregional progression-free survival rate was 38% and the overall survival rate 21%. A high minimum tumor dose and a small volume were independently associated with long survival in a multi-variable analysis. Conclusions: Most patients responded to BNCT. A high minimum tumor dose from BNCT was predictive for response and survival. (C) 2019 The Authors. Published by Elsevier B.V.Peer reviewe

A Novel Approach to Design and Evaluate BNCT Neutron Beams Combining Physical, Radiobiological, and Dosimetric Figures of Merit

Simple Summary Clinical potential and safety are presented as novel criteria to evaluate neutron beams designed for boron neutron capture therapy (BNCT). The presently used figures of merit are a set of physical quantities calculated in air, related to the neutron flux, the collimation, and the spectral characteristics. However, the capability of the beam to deliver an effective and safe treatment to patients should be the most important criterion in view of the clinical application. This work presents the design of a neutron beam produced by a proton accelerator coupled to a beryllium target and the use of new figures of merit to choose the best beam among different candidates. These figures of merit use tridimensional dosimetry simulated in phantoms and patients, to calculate the probability of tumor control without affecting healthy tissues, employing proper radiobiological models. Moreover, the dose absorbed by out-of-field healthy organs is used as a criterion to establish the safest beam for clinical treatments. Results show that beams that would be rejected by physical in-air quantities demonstrate a clinical performance comparable to existing neutron beams successfully used for patients, and that the presented criteria allow a clear selection of the most adequate beam among the ones presented. (1) Background:The quality of neutron beams for Boron Neutron Capture Therapy (BNCT) is currently defined by its physical characteristics in air. Recommendations exist to define whether a designed beam is useful for clinical treatment. This work presents a new way to evaluate neutron beams based on their clinical performance and on their safety, employing radiobiological quantities. (2) Methods: The case study is a neutron beam for deep-seated tumors from a 5 MeV proton beam coupled to a beryllium target. Physical Figures of Merit were used to design five beams; however, they did not allow a clear ranking of their quality in terms of therapeutic potential. The latter was then evaluated based on in-phantom dose distributions and on the calculation of the Uncomplicated Tumor Control Probability (UTCP). The safety of the beams was also evaluated calculating the in-patient out-of-beam dosimetry. (3) Results: All the beams ensured a UTCP comparable to the one of a clinical beam in phantom; the safety criterion allowed to choose the best candidate. When this was tested in the treatment planning of a real patient treated in Finland, the UTCP was still comparable to the one of the clinical beam. (4) Conclusions: Even when standard physical recommendations are not met, radiobiological and dosimetric criteria demonstrate to be a valid tool to select an effective and safe beam for patient treatment.Peer reviewe