Understanding the potentiality of accelerator based-boron neutron capture therapy for osteosarcoma: Dosimetry assessment based on the reported clinical experience

Background: Osteosarcoma is the most frequent primary malignant bone tumour, and its incidence is higher in children and adolescents, for whom it represents more than 10% of solid cancers. Despite the introduction of adjuvant and neo-adjuvant chemotherapy that markedly increased the success rate in the treatment, aggressive surgery is still needed and a considerable percentage of patients do not survive due to recurrences or early metastases. Boron Neutron Capture Therapy (BNCT), an experimental radiotherapy, was investigated as a treatment that could allow a less aggressive surgery by killing infiltrated tumour cells in the surrounding healthy tissues. BNCT requires an intense neutron beam to ensure irradiation times of the order of 1h. In Italy, a Radio Frequency Quadrupole (RFQ) proton accelerator has been designed and constructed for BNCT, and a suitable neutron spectrum was tailored by means of Monte Carlo calculations. This paper explores the feasibility of BNCT to treat osteosarcoma using this neutron source based on accelerator. Methods: The therapeutic efficacy of BNCT was analysed evaluating the dose distribution obtained in a clinical case of femur osteosarcoma. Mixed field dosimetry was assessed with two different formalisms whose parameters were specifically derived from radiobiological experiments involving in vitro UMR-106 osteosarcoma cell survival assays and boron concentration assessments in an animal model of osteosarcoma. A clinical case of skull osteosarcoma treated with BNCT in Japan was re-evaluated from the point of view of dose calculation and used as a reference for comparison. Results: The results in the case of femur osteosarcoma show that the RFQ beam would ensure a suitable tumour dose painting in a total irradiation time of less than an hour. Comparing the dosimetry between the analysed case and the treated patient in Japan it turns out that doses obtained in the femur tumour are at least as good as the ones delivered in the skull osteosarcoma. The same is concluded when the comparison is carried out taking into account osteosarcoma irradiations with photon radiation therapy. Conclusions: The possibility to apply BNCT to osteosarcoma would allow a multimodal treatment consisting in neo-adjuvant chemotherapy, high-LET selective radiation treatment and a more conservative surgery.Fil: Bortolussi, Silva. University of Pavia; ItaliaFil: Postuma, Ian. University of Pavia; ItaliaFil: Protti, Nicoletta. University of Pavia; ItaliaFil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Ferrari, Cinzia. University of Pavia; ItaliaFil: Cansolino, Laura. University of Pavia; ItaliaFil: Dionigi, Paolo. University of Pavia; ItaliaFil: Galasso, Olimpio. University of Catanzaro; ItaliaFil: Gasparini, Giorgio. University of Catanzaro; ItaliaFil: Altieri, Saverio. University of Pavia; ItaliaFil: Miyatake, Shin Ichi. Osaka Medical College; JapónFil: González, Sara Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentin

Extending neutron autoradiography technique for boron concentration measurements in hard tissues

The neutron autoradiography technique using polycarbonate nuclear track detectors (NTD) has been extended to quantify the boron concentration in hard tissues, an application of special interest in Boron Neutron Capture Therapy (BNCT). Chemical and mechanical processing methods to prepare thin tissue sections as required by this technique have been explored. Four different decalcification methods governed by slow and fast kinetics were tested in boron-loaded bones. Due to the significant loss of the boron content, this technique was discarded. On the contrary, mechanical manipulation to obtain bone powder and tissue sections of tens of microns thick proved reproducible and suitable, ensuring a proper conservation of the boron content in the samples. A calibration curve that relates the 10B concentration of a bone sample and the track density in a Lexan NTD is presented. Bone powder embedded in boric acid solution with known boron concentrations between 0 and 100 ppm was used as a standard material. The samples, contained in slim Lexan cases, were exposed to a neutron fluence of 1012 cm−2 at the thermal column central facility of the RA-3 reactor (Argentina). The revealed tracks in the NTD were counted with an image processing software. The effect of track overlapping was studied and corresponding corrections were implemented in the presented calibration curve. Stochastic simulations of the track densities produced by the products of the 10B thermal neutron capture reaction for different boron concentrations in bone were performed and compared with the experimental results. The remarkable agreement between the two curves suggested the suitability of the obtained experimental calibration curve. This neutron autoradiography technique was finally applied to determine the boron concentration in pulverized and compact bone samples coming from a sheep experimental model. The obtained results for both type of samples agreed with boron measurements carried out by ICP-OES within experimental uncertainties. The fact that the histological structure of bone sections remains preserved allows for future boron microdistribution analysis.Fil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Olivera, María Silvina. Comisión Nacional de Energía Atómica; ArgentinaFil: Saint Martin, María Laura Gisela. Comisión Nacional de Energía Atómica; ArgentinaFil: Rodriguez, Luis Miguel. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Fregenal, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Postuma, Ian. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Altieri, Saverio. Istituto Nazionale di Fisica Nucleare; Italia. Universita Degli Studi Di Pavia; ItaliaFil: González, Sara Josefina. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bortolussi, Silva. Istituto Nazionale di Fisica Nucleare; Italia. Universita Degli Studi Di Pavia; ItaliaFil: Portu, Agustina Mariana. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Meta-Review of Metanalytic Studies with Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Major Depression

BACKGROUND: Major Depression (MD) and treatment-resistant depression (TRD) are worldwide leading causes of disability and therapeutic strategies for these impairing and prevalent conditions include pharmacological augmentation strategies and brain stimulation techniques. In this perspective, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique with a favorable profile of tolerability which, despite being recently approved by the Food and Drug Administration (FDA) for the treatment of patients with medication-refractory unipolar depression, still raises some doubts about most effective parameters of stimulation.METHODS: A literature search was performed using PubMed for the years 2001 through February 2011 in order to review meta-analytic studies assessing efficacy and safety issues for rTMS in depressive disorders. Fifteen meta-analyses were identified and critically discussed in order to provide an updated and comprehensive overview of the topic with specific emphasis on potentially optimal parameters of stimulation.RESULTS: First meta-analyses on the efficacy of rTMS for the treatment of MD and TRD have shown mixed results. On the other hand, more recent meta-analytic studies seem to support the antidepressant efficacy of the technique to a greater extent, also in light of longer periods of stimulation (e.g. > 2 weeks).CONCLUSION: rTMS seems to be an effective and safe brain stimulation technique for the treatment of medication refractory depression. Nevertheless, further studies are needed to better define specific stimulation-related issues, such as duration of treatment as well as durability of effects and predictors of response

Exploring Boron Neutron Capture Therapy for non-small cell lung cancer

Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with 10B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells.The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced.Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments.The optimal neutron energy is within [500eV-3keV], lower than the 10keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases.Conclusions drawn from [Suzuki etal., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options.Fil: Farías, Rubén Oscar. Comisión Nacional de Energía Atómica. Gerencia del Área de Investigación y Aplicaciones No Nucleares. Gerencia Física (Centro Atómico Constituyentes). Proyecto Tandar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bortolussi, Silva. Università degli Studi di Pavia; ItaliaFil: Bonvicini Menéndez, Pablo Federico. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; ArgentinaFil: González, Sara Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica. Gerencia del Área de Investigación y Aplicaciones No Nucleares. Gerencia Física (Centro Atómico Constituyentes). Proyecto Tandar; Argentin

Abstract ID: 51 Monte Carlo optimization of a neutron beam from 5 MeV 9 Be(p,n) 9 B reaction for clinical BNCT

Boron Neutron Capture Therapy (BNCT) is an experimental radiotherapy that uses the combination of neutron irradiation and 10B to treat neoplasms. By means of this technique, many clinical trials were performed worldwide with promising results [1] using research nuclear reactors as neutron sources. Anyhow, these machines have several problems that hinder the development of dedicated BNCT hospitals. This issue can now be overcome by using intense-current proton accelerators, which coupled with beryllium or lithium targets yield more than 1014 neutron per second. This can be a boost to BNCT because accelerators are more compact and can be installed within hospitals.The Italian National Institute of Nuclear Physics (INFN) designed and manufactured a Radiofrequency Quadrupole proton accelerator (RFQ) [2], which delivers 5 MeV protons with 30 mA current in a Continuous Wave (CW) mode and it is coupled to a beryllium target. This accelerator could be installed at Centro Nazionale di Adroterapia Oncologica (CNAO) in Pavia.In this work we present the MC calculations for the tailoring of a BNCT neutron beam obtained by the described RFQ. Firstly, we show that MC transport codes such as MCNP and PHITS are not able to simulate the correct neutron spectra from 5 MeV protons interacting on beryllium. Therefore, the neutron double differential source implemented in MCNP was extracted from the measurements performed by Agosteo et al. [3]. As the energy range goes up to 3.5 MeV, neutrons need to be moderated and collimated by a Beam Shaping Assembly (BSA), because BNCT requires a spectrum peaked between 1 and 10 keV. Differently from the past, where the optimal configuration was chosen according to physical characteristics of the beam, in this case the results were evaluated on the basis of the dosimetry obtained in a real clinical case by treatment planning simulation. What emerges, is that the classical figures of merit employed for the tailoring of a clinical BNCT [4] should be taken as a first guideline, while the dosimetric assessment on realistic clinical scenarios is the most appropriate criterion for beam evaluations.Fil: Postuma, I.. Unit of Pavia; ItaliaFil: Bortolussi, S.. University of Pavia; ItaliaFil: Protti, N.. Unit of Pavia; ItaliaFil: Fatemi, S.. Unit of Pavia; Italia. University of Pavia; ItaliaFil: González, Sara Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Battistoni, G.. Unit of Milan; ItaliaFil: Altieri, S.. Unit of Pavia; Italia. University of Pavia; Itali

The essential role of radiobiological figures of merit for the assessment and comparison of beam performances in boron neutron capture therapy

Purpose: Boron Neutron Capture Therapy (BNCT) is a treatment modality that uses an external neutron beam to selectively inactive boron10-loaded tumor cells. This work presents the development and innovative use of radiobiological probability models to adequately evaluate and compare the therapeutic potential and versatility of beams presenting different neutron energy spectra. M&M: Aforementioned characteristics, collectively refer to as the performance of a beam, were defined on the basis of radiobiological probability models for the first time in BNCT. A model of uncomplicated tumor control probability (UTCP) for HN cancer was introduced. This model considers a NTCP able to predict severe mucositis and a TCP for non-uniform doses derived herein. A systematic study comprising a simplified HN cancer model is presented as a practical application of the introduced radiobiological figures of merit (FOM) for assessing and comparing the performance of different clinical beams. Applications involving treated HN cancer patients were also analyzed. Results: The maximum UTCP proved suitable and sensitive to assess the performance of a beam, revealing particularities of the studied sources that the physical FOMs do not highlight. The radiobiological FOMs evaluated in patients showed to be useful tools both for retrospective analysis of the BNCT treatments, and for prospective studies of beam optimization and feasibility. Conclusions: The presented developments and applications demonstrated that it is possible to assess and compare performances of completely different beams fairly and adequately by assessing the radiobiological FOM UTCP. Thus, this figure would be a practical and essential aid to guide treatment decisions.Fil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Koivunoro, H.. No especifíca;Fil: Postuma, I.. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Longhino, Juan Manuel. Comisión Nacional de Energía Atómica; ArgentinaFil: Boggio, Esteban Fabián. Comisión Nacional de Energía Atómica; ArgentinaFil: Farías, R. O.. Universidad Favaloro; ArgentinaFil: Bortolussi, Silva. Istituto Nazionale di Fisica Nucleare; Italia. Universita degli Studi di Pavia; ItaliaFil: González, Sara Josefina. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Charged particle spectrometry to measure 10B concentration in bone

Osteosarcoma is the most common primary malignant tumour of bone in young patients. The survival of these patients has largely been improved due to adjuvant and neo-adjuvant chemotherapy in addition to surgery. Boron neutron capture therapy (BNCT) is proposed as a complementary therapy, due to its ability to inactivate tumour cells that may survive the standard treatment and that may be responsible for recurrences and/or metastases. BNCT is based on neutron irradiation of a tumour enriched in 10 B with a boron-loaded drug. Low-energy neutron capture in 10 B creates charged particles that impart a high dose to tumour cells, which can be calculated only knowing the boron concentration. Charged particle spectrometry is a method that can be used to quantify boron concentration. This method requires acquisition of the energy spectra of charged particles such as alpha particles produced by neutron capture reactions in thin tissue sections irradiated with low-energy neutrons. Boron concentration is then determined knowing the stopping power of the alpha particles in the sample material. This paper describes the adaptation of this method for bone, with emphasis on sample preparation, experimental set-up and stopping power assessment of the involved alpha particles. The knowledge of boron concentration in healthy bones is important, because it allows for any dose limitation that might be necessary to avoid adverse effects such as bone fragility. The measurement process was studied through Monte Carlo simulations and analytical calculations. Finally, the boron content of bone samples was measured by alpha spectrometry at the TRIGA reactor in Pavia, Italy, and compared to that obtained by neutron autoradiography. The agreement between the results obtained with these techniques confirms the suitability of alpha spectrometry to measure boron in bone.Fil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Bortolussi, Silva. Universita Degli Studi Di Pavia; Italia. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: González, Sara Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Postuma, Ian. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Protti, Nicoletta. Istituto Nazionale Di Fisica Nucleare.; ItaliaFil: Portu, Agustina Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Olivera, María Silvina. Comisión Nacional de Energía Atómica; ArgentinaFil: Rodriguez, Luis Miguel. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fregenal, Daniel Eduardo. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Altieri, Saverio. Istituto Nazionale Di Fisica Nucleare.; Italia. Universita Degli Studi Di Pavia; Itali

Comparison of Photon Isoeffective Dose Models Based on In Vitro and In Vivo Radiobiological Experiments for Head and Neck Cancer Treated with BNCT

Boron neutron capture therapy (BNCT) is a treatment modality for cancer that involves radiations of different qualities. A formalism that proved suitable to compute doses in photon-equivalent units is the photon isoeffective dose model. This study addresses the question whether considering in vitro or in vivo radiobiological studies to determine the parameters involved in photon isoeffective dose calculations affects the consistency of the model predictions. The analysis is focused on head and neck squamous cell carcinomas (HNSCC), a main target that proved to respond to BNCT. The photon isoeffective dose model for HNSCC with parameters from in vitro studies using the primary human cell line UT-SCC-16A was introduced and compared to the one previously reported with parameters from an in vivo oral cancer model in rodents. Both models were first compared in a simple scenario by means of tumor dose and control probability calculations. Then, the clinical impact of the different dose models was assessed from the analysis of a group of squamous cell carcinomas (SCC) patients treated with BNCT. Traditional dose calculations using the relative biological effectiveness factors derived from the SCC cell line were also analyzed. Predictions of tumor control from the evaluated models were compared to the patients' outcome. The quantification of the biological effectiveness of the different radiations revealed that relative biological effectiveness/compound biological effectiveness (RBE/CBE) factors for the SCC cell line are up to 20% higher than those assumed in clinical BNCT, highlighting the importance of using experimental data intimately linked to the tumor type to derive the model's parameters. The comparison of the different models showed that photon isoeffective doses based on in vitro data are generally greater than those from in vivo data (∼8-16% for total tumor absorbed doses of 10-15 Gy). However, the predictive power of the two models was not affected by these differences: both models fulfilled conditions to guarantee a good predictive performance and gave predictions statistically compatible with the clinical outcome. On the other hand, doses computed with the traditional model were substantially larger than those obtained with both photon isoeffective models. Moreover, the traditional model is statistically rejected, which reinforces the assertion that its inconsistencies are intrinsic and not due to the use of RBE/CBE factors obtained for a tumor type different from HN cancer. The results suggest that the nature of the radiobiological data would not affect the consistency of the photon isoeffective dose model in the studied cases of SCC head and neck cancer treated with BPA-based BNCT.Fil: Perotti Bernardini, Giuliano Franco. Comisión Nacional de Energía Atómica; ArgentinaFil: Bortolussi, Silva. Universita degli Studi di Pavia; ItaliaFil: Koivunoro, Hanna. University of Helsinki; FinlandiaFil: Provenzano, Lucas. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ferrari, Cinzia. Universita degli Studi di Pavia; ItaliaFil: Cansolino, Laura. Universita degli Studi di Pavia; ItaliaFil: Postuma, Ian. Universita degli Studi di Pavia; ItaliaFil: Carando, Daniel Germán. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigaciones Matemáticas "Luis A. Santaló". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Matemáticas "Luis A. Santaló"; ArgentinaFil: Kankaanranta, Leena. University of Helsinki; FinlandiaFil: Joensuu, Heikki. University of Helsinki; FinlandiaFil: González, Sara Josefina. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin