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1.
Med Phys ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737870

RESUMO

PURPOSE: Particle therapy is becoming increasingly available world-wide for precise tumour targeting, its favourable depth dose deposition, and increased biological damage to tumour tissue compared to conventional photon therapy. As demand increases for improved robustness and conformality, next-generation secondary dose calculation engines are needed to verify treatment plans independently and provide estimates for clinical decision-making factors, such as dose-averaged linear energy transfer (LETd ) and relative biological effectiveness (RBE). METHOD: FRoG (Fast dose Recalculation on GPU) has been installed and commissioned at the Danish Centre for Particle Therapy (DCPT). FRoG was developed for synchrotron-based facilities and has previously demonstrated good agreement with gold-standard Monte Carlo simulations and measurements. In this work, additions and modifications to FRoG's pencil beam algorithm to support the ion beam delivery with cyclotron-based technology as used at the DCPT, range shifter (RS) implementation and robustness analysis methods are presented. FRoG dose predictions are compared to measurements and predictions of the clinical treatment planning system (TPS) Eclipse (Varian Medical Systems, Palo Alto, United States of America, CA, v.13.7.16) in both homogenous and heterogeneous scenarios using a solid-water and a half-head anthropomorphic phantom, respectively. Additional capabilities of FRoG are explored by performing a plan robustness analysis, analysing dose and LETd for ten patients. RESULTS: Mid-target measurements in spread-out Bragg Peaks (SOBP) were on average within -0.19% ± 0.30% and < 0.5% of FRoG predictions for irradiations without and with RS, respectively. Average 3%/2mm 3D γ-analysis passing rates were 99.1% for ~200 patient plan QA comparisons. Measurement with an anthropomorphic head-phantom yielded a γ-passing rate >98%. Overall, maximum target differences in D02% of <2% between the TPS and FRoG were observed for patient plans. The robustness analysis study accounting for range, delivery, and positioning uncertainties revealed small differences in mean target dose and a maximum LETd VH02% (LETd received by 2% of the volume having dose larger than 1% of maximum dose) values below 10.1keV/µm to the brain stem. CONCLUSION: We demonstrate that auxiliary dose calculation systems like FRoG can yield excellent agreement to measurements comparable to clinical beam models. Through this work, application of FRoG as a secondary engine at third party cyclotron-based particle treatment facilities is now established for dose verification as well as providing further insight on LETd and variable RBE distributions for protons, currently absent from the standard clinical TPS.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32504659

RESUMO

PURPOSE: Present-day treatment planning in carbon ion therapy is conducted with assumptions for a limited number of tissue types and models for effective dose. Here, we comprehensively assess relative biological effectiveness (RBE) in carbon ion therapy and associated models toward the modernization of current clinical practice in effective dose calculation. METHODS: Using 2 human (A549, H460) and 2 mouse (B16, Renca) tumor cell lines, clonogenic cell survival assay was performed for examination of changes in RBE along the full range of clinical-like spread-out Bragg peak (SOBP) fields. Prediction power of the local effect model (LEM1 and LEM4) and the modified microdosimetric kinetic model (mMKM) was assessed. Experimentation and analysis were carried out in the frame of a multidimensional end point study for clinically relevant ranges of physical dose (D), dose-averaged linear energy transfer (LETd), and base-line photon radio-sensitivity (α/ß)x. Additionally, predictions were compared against previously reported RBE measurements in vivo and surveyed in patient cases. RESULTS: RBE model prediction performance varied among the investigated perspectives, with mMKM prediction exhibiting superior agreement with measurements both in vitro and in vivo across the 3 investigated end points. LEM1 and LEM4 performed their best in the highest LET conditions but yielded overestimations and underestimations in low/midrange LET conditions, respectively, as demonstrated by comparison with measurements. Additionally, the analysis of patient treatment plans revealed substantial variability across the investigated models (±20%-30% uncertainty), largely dependent on the selected model and absolute values for input tissue parameters αx and ßx. CONCLUSION: RBE dependencies in vitro, in vivo, and in silico were investigated with respect to various clinically relevant end points in the context of tumor-specific tissue radio-sensitivity assignment and accurate RBE modeling. Discovered model trends and performances advocate upgrading current treatment planning schemes in carbon ion therapy and call for verification via clinical outcome analysis with large patient cohorts.

3.
Int J Radiat Oncol Biol Phys ; 106(1): 194-205, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610250

RESUMO

PURPOSE: To develop and validate combined ion-beam with constant relative biological effectiveness (RBE) (CICR) particle therapy in single field arrangements for improved treatment efficacy, robustness, and normal tissue sparing. METHODS AND MATERIALS: The PRECISE (PaRticle thErapy using single and Combined Ion optimization StratEgies) treatment planning system was developed to investigate clinical viability of CICR treatments. Single-field uniform dose (SFUD) with a single ion (proton [p], helium [He], or carbon [C]) and CICR (C-p and C-He) treatments were generated for 3 patient cases with a clinically prescribed dose of 3 Gy (RBE) per fraction. Spread-out Bragg peak plans were irradiated in homogenous and clinical-like settings using an anthropomorphic head phantom. A dosimetric and biological verification of CICRC-p treatments using a murine glioma cell line (GL261) was performed. RESULTS: CICR treatment plans for the 3 patients presented highly uniform physical dose while reducing high dose-averaged linear energy transfer gradients compared with carbon ions alone. When considering uncertainty in tissue parameter (α/ß)x assignment and RBE modeling, the CICRC-p treatment exhibited enhanced biophysical stability within the target volume, similar to protons alone. CICR treatments reduced dose to normal tissue surrounding the target, exhibiting similar or improved dosimetric features compared with SFUDHe. For both CICRC-p and SFUD treatments, measurements verified the planned dose in the target within ∼3%. Planned versus measured target RBE values were 1.38 ± 0.02 and 1.39 ± 0.07 (<1% deviation), respectively, for the CICRC-p treatment in heterogenous settings. CONCLUSIONS: Here, we demonstrate that by combining 2 (or more) ions in a single field arrangement, more robust biological and more conformal dose distributions can be delivered compared with conventional particle therapy treatment planning. This work constitutes the first dosimetric and biological verification of multi-ion particle therapy in homogeneous as well as heterogenous settings.


Assuntos
Neoplasias Encefálicas/radioterapia , Carcinoma Adenoide Cístico/radioterapia , Cordoma/radioterapia , Glioma/radioterapia , Radioterapia com Íons Pesados/métodos , Tratamentos com Preservação do Órgão/métodos , Neoplasias da Coluna Vertebral/radioterapia , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Carbono/uso terapêutico , Carcinoma Adenoide Cístico/diagnóstico por imagem , Linhagem Celular Tumoral , Cordoma/diagnóstico por imagem , Terapia Combinada/métodos , Fracionamento da Dose de Radiação , Glioma/diagnóstico por imagem , Hélio/uso terapêutico , Humanos , Transferência Linear de Energia , Camundongos , Órgãos em Risco , Imagens de Fantasmas , Terapia com Prótons/métodos , Lesões por Radiação/prevenção & controle , Planejamento da Radioterapia Assistida por Computador , Eficiência Biológica Relativa , Sacro , Neoplasias da Coluna Vertebral/diagnóstico por imagem
4.
Front Oncol ; 9: 798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508363

RESUMO

Background: Ionizing radiation was shown to be able to influence the function of cardiac implantable electronic devices (CIED's) leading to malfunctions with potentially severe consequences. Those effects presumably correlate with beam energy and neutron production. Thus, particle facilities are commonly cautious to treat patients with CIED's with particles, but substantial evidence is lacking. Methods and Materials: In total 31 patients were investigated, who have been treated at the Heidelberg Ion-Beam Therapy Center (HIT) from September 2012 to February 2019 with protons and carbon ions in active-scanning technique. All CIED's were checked after every single irradiation by the department of cardiology. The minimum distance between the CIED and the planning target volume (PTV), the 10% isodose and the single beam in Beam's Eye View (BEV) was analyzed for 12 patients. Results: In total, 31 patients received 32 courses of radiotherapy (RT). Twenty-two received treatment with carbon ion beam and ten with proton beam. The cumulative number of fractions was 582, the cumulative number of documented controls after RT was 504 (87%). Three patients had an implantable cardioverter-defibrillator (ICD) and 28 patients had a pacemaker at the time of treatment. Seven patients had a heart rate of ≤30/min. The majority of patients (69%) were treated for tumors of the head and neck. The median minimum distance between CIED and PTV, 10% isodose and the single beam on BEV was 13.4, 11.6, and 8.3 cm, respectively. There were no registered events associated with the treatment in this evaluation. Conclusion: Treatment of CIED-patients with protons and carbon ions applied with active raster scanning technique was safe without any incidents in our single center experience. Monitoring after almost every fraction provided systematic and extensive data. Further investigations are necessary in order to form reliable guidelines, which should consider different modes of beam application, as active scanning supposedly provides a greater level of safety from malfunctions for patients with CIED undergoing particle irradiation.

5.
Phys Med ; 64: 123-131, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31515011

RESUMO

With high-precision radiotherapy on the rise towards mainstream healthcare, comprehensive validation procedures are essential, especially as more sophisticated technologies emerge. In preparation for the upcoming translation of novel ions, case-/disease-specific ion-beam selection and advanced multi-particle treatment modalities at the Heidelberg Ion-beam Therapy Center (HIT), we quantify the accuracy limits in particle therapy treatment planning under complex heterogeneous conditions for the four ions (1H, 4He, 12C, 16O) using a Monte Carlo Treatment Planning platform (MCTP), an independent GPU-accelerated analytical dose engine developed in-house (FRoG) and the clinical treatment planning system (Syngo RT Planning). Attaching an anthropomorphic half-head Alderson RANDO phantom to entrance window of a dosimetric verification water tank, a cubic target spread-out Bragg peak (SOBP) was optimized using the MCTP to best resolve effects of anatomic heterogeneities on dose homogeneity. Subsequent forward calculations were executed in FRoG and Syngo. Absolute and relative dosimetry was performed in the experimental beam room using 1D and 2D array ionization chamber detectors. Mean absolute percent deviation in dose (|%Δ|) between predictions and PinPoint ionization chamber measurements were within ∼2% for all investigated ions for both MCTP and FRoG. For protons and carbon ions, |%Δ| values were ∼4% for Syngo. For the four ions, 3D-γ analysis (3%/3mm criteria) of FLUKA and FRoG presented mean passing rates of 97.0(±2.4)% and 93.6(±4.2)%. FRoG demonstrated satisfactory agreement with gold standard Monte Carlo simulation and measurement, superior to the commercial system. Our pre-clinical trial landmarks the first measurements taken in anthropomorphic settings for helium, carbon and oxygen ion-beam therapy.


Assuntos
Radioterapia com Íons Pesados/instrumentação , Método de Monte Carlo , Imagens de Fantasmas , Humanos , Radiometria , Planejamento da Radioterapia Assistida por Computador
6.
Radiat Oncol ; 14(1): 123, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296232

RESUMO

BACKGROUND: Helium (4He) ion beam therapy provides favorable biophysical characteristics compared to currently administered particle therapies, i.e., reduced lateral scattering and enhanced biological damage to deep-seated tumors like heavier ions, while simultaneously lessened particle fragmentation in distal healthy tissues as observed with lighter protons. Despite these biophysical advantages, raster-scanning 4He ion therapy remains poorly explored e.g., clinical translational is hampered by the lack of reliable and robust estimation of physical and radiobiological uncertainties. Therefore, prior to the upcoming 4He ion therapy program at the Heidelberg Ion-beam Therapy Center (HIT), we aimed to characterize the biophysical phenomena of 4He ion beams and various aspects of the associated models for clinical integration. METHODS: Characterization of biological effect for 4He ion beams was performed in both homogenous and patient-like treatment scenarios using innovative models for estimation of relative biological effectiveness (RBE) in silico and their experimental validation using clonogenic cell survival as the gold-standard surrogate. Towards translation of RBE models in patients, the first GPU-based treatment planning system (non-commercial) for raster-scanning 4He ion beams was devised in-house (FRoG). RESULTS: Our data indicate clinically relevant uncertainty of ±5-10% across different model simulations, highlighting their distinct biological and computational methodologies. The in vitro surrogate for highly radio-resistant tissues presented large RBE variability and uncertainty within the clinical dose range. CONCLUSIONS: Existing phenomenological and mechanistic/biophysical models were successfully integrated and validated in both Monte Carlo and GPU-accelerated analytical platforms against in vitro experiments, and tested using pristine peaks and clinical fields in highly radio-resistant tissues where models exhibit the greatest RBE uncertainty. Together, these efforts mark an important step towards clinical translation of raster-scanning 4He ion beam therapy to the clinic.


Assuntos
Carcinoma de Células Renais/radioterapia , Hélio/uso terapêutico , Neoplasias Renais/radioterapia , Método de Monte Carlo , Planejamento da Radioterapia Assistida por Computador/métodos , Carcinoma de Células Renais/patologia , Sobrevivência Celular , Radioterapia com Íons Pesados , Humanos , Neoplasias Renais/patologia , Dosagem Radioterapêutica , Eficiência Biológica Relativa , Células Tumorais Cultivadas
7.
Strahlenther Onkol ; 195(7): 677-687, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30972453

RESUMO

PURPOSE: Current research approaches in lymphoma focus on reduction of therapy-associated long-term side effects. Especially in mediastinal lymphoma, proton beam radiotherapy (PT) may be a promising approach for reducing the dose to organs at risk (OAR). PATIENTS: In total, 20 patients were irradiated with active scanning PT at Heidelberg Ion Beam Therapy Center (HIT) between September 2014 and February 2017. For comparative analysis, additional photon irradiation plans with helical intensity-modulated radiotherapy (IMRT) were calculated and quantitative and qualitative dose evaluations were made for both treatment modalities. Toxicity and survival outcomes were evaluated. RESULTS: Clinical target volume coverage was comparable in both treatment modalities and did not significantly differ between IMRT and PT. Nevertheless, PT showed superiority regarding the homogeneity index (HIPT = 1.041 vs. HIIMRT = 1.075, p < 0.001). For all OAR, PT showed significantly higher dose reductions compared with IMRT. In particular, the dose to the heart was reduced in PT (absolute dose reduction of Dmean of 3.3 Gy [all patients] and 4.2 Gy [patients with pericardial involvement]). Likewise, the subgroup analysis of female patients, who were expected to receive higher doses to the breast, showed a higher dose reduction in Dmean of 1.2 Gy (right side) and 2.2 Gy (left side). After a median follow-up of 32 months (range 21-48 months), local and distant progression free survival (LPFS and DPFS) were 95.5% and 95.0%, respectively. Radiotherapy was tolerated well with only mild (grade 1-2) radiation-induced acute and chronic side effects. CONCLUSION: A significant reduction in the dose to the surrounding OAR was achieved with PT compared with photon irradiation, without compromising target volume coverage. Dosimetric advantages may have the potential to translate into a reduction of long-term radiation-induced toxicity in young patients with malignant lymphoma of the mediastinum.


Assuntos
Doença de Hodgkin/radioterapia , Linfoma não Hodgkin/radioterapia , Neoplasias do Mediastino/radioterapia , Terapia com Prótons/métodos , Radiometria/métodos , Radioterapia de Intensidade Modulada/métodos , Adolescente , Adulto , Feminino , Seguimentos , Doença de Hodgkin/patologia , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Órgãos em Risco/efeitos da radiação , Resultado do Tratamento , Adulto Jovem
8.
Sci Rep ; 8(1): 14829, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287930

RESUMO

Radiotherapy with protons and heavier ions landmarks a novel era in the field of high-precision cancer therapy. To identify patients most benefiting from this technologically demanding therapy, fast assessment of comparative treatment plans utilizing different ion species is urgently needed. Moreover, to overcome uncertainties of actual in-vivo physical dose distribution and biological effects elicited by different radiation qualities, development of a reliable high-throughput algorithm is required. To this end, we engineered a unique graphics processing unit (GPU) based software architecture allowing rapid and robust dose calculation. FRoG, Fast Recalculation on GPU, currently operates with four particle beams available at Heidelberg Ion Beam Therapy center, i.e., raster-scanning proton (1H), helium (4He), carbon (12C) and oxygen ions (16O). FRoG enables comparative analysis of different models for estimation of physical and biological effective dose in 3D within minutes and in excellent agreement with the gold standard Monte Carlo (MC) simulation. This is a crucial step towards development of next-generation patient specific radiotherapy.

9.
Acta Oncol ; 57(12): 1713-1720, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30264630

RESUMO

BACKGROUND: The purpose of this study was to compare dosimetric differences related to target volume and organs-at-risk (OAR) using 3D-conformal radiotherapy (3DCRT), volumetric modulated arc therapy (VMAT), TomoTherapy (Tomo), proton radiotherapy (PRT), and carbon ion radiotherapy (CIRT) as part of postoperative thymoma irradiation. MATERIAL AND METHODS: This single-institutional analysis included 10 consecutive patients treated with adjuvant radiotherapy between December 2013 and September 2016. CT-datasets and respective RT-structures were anonymized and plans for all investigated RT modalities (3DCRT, VMAT, Tomo, PRT, CIRT) were optimized for a total dose of 50 Gy in 25 fractions. Comparisons between target volume and OAR dosimetric parameters were performed using the Wilcoxon rank-sum test. RESULTS: The best target volume coverage (mean PTV V95% for all patients) was observed for Tomo (97.9%), PRT (97.6%), and CIRT (96.6%) followed by VMAT (85.4%) and 3DCRT (74.7%). PRT and CIRT both significantly reduced mean doses to the lungs, breasts, heart, and esophagus, as well as the spinal cord maximum dose compared with photon modalities. Among photon-based techniques, VMAT showed improved OAR sparing over 3DCRT. Tomo was associated with considerable low-dose exposure to the lungs, breasts, and heart. CONCLUSIONS: Particle radiotherapy (PRT, CIRT) showed superior OAR sparing and optimal target volume coverage. The observed dosimetric advantages are expected to reduce toxicity rates. However, their clinical impact must be investigated prospectively.


Assuntos
Tratamentos com Preservação do Órgão/métodos , Órgãos em Risco/efeitos da radiação , Fótons/efeitos adversos , Terapia com Prótons/efeitos adversos , Timoma/terapia , Neoplasias do Timo/terapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tratamentos com Preservação do Órgão/efeitos adversos , Fótons/uso terapêutico , Período Pós-Operatório , Terapia com Prótons/métodos , Lesões por Radiação/prevenção & controle , Radiometria , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/métodos , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Timectomia , Timo/patologia , Timo/cirurgia , Neoplasias do Timo/patologia , Adulto Jovem
10.
Cancer ; 124(9): 2036-2044, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29469932

RESUMO

BACKGROUND: The current study compares the results of irradiation with protons and irradiation with carbon ions via a raster scan technique in patients with G1 and G2 skull base chondrosarcomas. METHODS: Between 2009 and 2014, a total of 101 patients (40 men and 61 women) with a median age of 44 years (range, 19-77 years) were irradiated with carbon ions (79 patients) or protons (22 patients) via a raster scan technique at the Heidelberg Ion Beam Therapy Center. The median total dose was 60 Gy (relative biological effectiveness [RBE]) at 3 Gy per fraction for carbon ions and 70 Gy (RBE) at 2 Gy per fraction for protons. The median boost planning target volume was 38 cm3 (range, 8-133 cm3 ). Overall survival (OS) and local control (LC) were evaluated with the Kaplan-Meier method. RESULTS: The median follow-up period was 40 months (range, 0.8-78.1 months). At the start of the irradiation, all patients had residual macroscopic tumors. Five patients (5%) developed a local recurrence during the follow-up. The 1-, 2-, and 4-year LC rates were 100%, 100%, and 100%, respectively, for protons and 98.6%, 97.2%, and 90.5%, respectively, for carbon ions. The OS rates during the same periods of time were 100%, 100%, and 100%, respectively, for protons and 100%, 98.5%, and 92.9%, respectively, for carbon ions. An age ≤ 44 years was associated with a trend for a better outcome. No toxicity worse than Common Toxicity Criteria grade 3 was observed after treatment. CONCLUSIONS: No significant difference between carbon ions and protons in the therapy of skull base chondrosarcoma could be detected in these initial retrospective results. Cancer 2018;124:2036-44. © 2018 American Cancer Society.


Assuntos
Radioisótopos de Carbono , Condrossarcoma/radioterapia , Radioterapia com Íons Pesados/métodos , Prótons , Radioterapia de Intensidade Modulada/métodos , Neoplasias da Base do Crânio/radioterapia , Adulto , Fatores Etários , Idoso , Condrossarcoma/mortalidade , Fracionamento da Dose de Radiação , Feminino , Seguimentos , Alemanha/epidemiologia , Radioterapia com Íons Pesados/efeitos adversos , Radioterapia com Íons Pesados/instrumentação , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/instrumentação , Estudos Retrospectivos , Neoplasias da Base do Crânio/mortalidade , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
11.
Radiat Oncol ; 13(1): 2, 2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29316969

RESUMO

BACKGROUND: Due to their favorable physical and biological properties, helium ion beams are increasingly considered a promising alternative to proton beams for radiation therapy. Hence, this work aims at comparing in-silico the treatment of brain and ocular meningiomas with protons and helium ions, using for the first time a dedicated Monte Carlo (MC) based treatment planning engine (MCTP) thoroughly validated both in terms of physical and biological models. METHODS: Starting from clinical treatment plans of four patients undergoing proton therapy with a fixed relative biological effectiveness (RBE) of 1.1 and a fraction dose of 1.8 Gy(RBE), new treatment plans were optimized with MCTP for both protons (with variable and fixed RBE) and helium ions (with variable RBE) under the same constraints derived from the initial clinical plans. The resulting dose distributions were dosimetrically compared in terms of dose volume histograms (DVH) parameters for the planning target volume (PTV) and the organs at risk (OARs), as well as dose difference maps. RESULTS: In most of the cases helium ion plans provided a similar PTV coverage as protons with a consistent trend of superior OAR sparing. The latter finding was attributed to the ability of helium ions to offer sharper distal and lateral dose fall-offs, as well as a more favorable differential RBE variation in target and normal tissue. CONCLUSIONS: Although more studies are needed to investigate the clinical potential of helium ions for different tumour entities, the results of this work based on an experimentally validated MC engine support the promise of this modality with state-of-the-art pencil beam scanning delivery, especially in case of tumours growing in close proximity of multiple OARs such as meningiomas.


Assuntos
Hélio/uso terapêutico , Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Terapia com Prótons/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Humanos , Íons/uso terapêutico , Método de Monte Carlo , Eficiência Biológica Relativa
12.
Radiat Oncol ; 12(1): 208, 2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29287602

RESUMO

BACKGROUND: Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions. METHODS: Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs. normoxic conditions (21% O2). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi). RESULTS: The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition. CONCLUSIONS: Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/terapia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Radioterapia com Íons Pesados , Proteínas Nucleares/antagonistas & inibidores , Tolerância a Radiação/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Hipóxia Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia , Relação Dose-Resposta à Radiação , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Fótons/uso terapêutico , Radiossensibilizantes , Células Tumorais Cultivadas
13.
Radiother Oncol ; 125(2): 266-272, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29050959

RESUMO

PURPOSE: To retrospectively assess the feasibility and safety of a sequential proton boost following conventional chemoradiation in high-grade glioma (HGG). METHOD AND MATERIALS: Sixty-six consecutive patients with HGG were treated with 50.0 Gy photons (50.0-50.4 Gy) in 2.0 Gy (1.8-2.0 Gy) fractions, followed by a proton boost with 10 Gy equivalent (Gy(RBE)) in 2.0 Gy(RBE) fractions. Patients were matched one to one with 66 patients with HGG undergoing conventional radiation therapy (RT) with 60.0 Gy photons (59.4-60.0 Gy) in 2.0 Gy fractions (1.8-2.0 Gy). Matching criteria were age, WHO grade, Karnofsky's performance status, PTV size, temozolomide therapy (each p > 0.1). The study assessed progression-free survival (PFS), overall survival (OS), acute treatment-related toxicity (CTCAE v.4.03) and pseudoprogression (RANO criteria). RESULTS: Median PFS and OS were similar in both treatment groups (bimodality RT, PFS: 8.8 months [2-32 months], OS 19.1 months [4-41 months]; photon-only RT, PFS: 7.2 months [2-39 months], 20.9 months [3-53 months]; p = 0.430 and p = 0.125). The median PTV of the proton boost was significantly smaller than the photon plan PTVs (each p < 0.001). Acute toxicity was mild. Toxicity ≥grade 2 was observed in 6 patients (9%) receiving bimodality RT and 9 patients (14%) receiving photon-only RT. Two types of severe adverse events (CTCAE grade 3) occurred solely in the photon-only group: severe increase in intracranial pressure (5%); and generalized seizures (3%). Pseudoprogression was rare, occurring on average 6 weeks after radiotherapy, and was balanced in both treatment groups (n = 4 each; 8%). CONCLUSION: Delivering a proton boost to significantly smaller target volumes when compared to photon-only plans, yielded comparable progression and survival rates at lower CTCAE grade 3 acute toxicity rates. Pseudoprogression occurred rarely and evenly distributed in both treatment groups. Thus, bimodality RT was at least equivalent regarding outcome and potentially superior with respect to toxicity in patients with HGG. SUMMARY: Treating patients with HGG with 50.0 Gy photons in 2.0 Gy fractions, followed by a proton boost with 10 Gy(RBE) in 2.0 Gy(RBE) fractions, is safe and feasible. Severe radiation-induced acute toxicity and pseudoprogression were rare in both treatment groups. Therefore, in this clinical setting, combined proton radiotherapy might be beneficial in terms of further risk reduction for treatment-related side effects. Interestingly, treatment volume reduction using a proton boost led to comparable survival and progression rates with decreased severe treatment-related toxicity compared to conventional photon radiotherapy.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioma/radioterapia , Terapia com Prótons/métodos , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/cirurgia , Quimiorradioterapia Adjuvante , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Glioma/tratamento farmacológico , Glioma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Terapia com Prótons/efeitos adversos , Estudos Retrospectivos , Temozolomida , Adulto Jovem
14.
Front Oncol ; 7: 35, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28348976

RESUMO

BACKGROUND: This work investigates on putative cytotoxic effects in four different hepatocellular carcinoma (HCC) cell lines after irradiation with photons or carbon ions in combination with new targeted molecular therapy using either Temsirolimus (TEM) or Gemcitabine (GEM). METHODS AND MATERIALS: The HCC cell lines HepG2, Hep3B, HuH7, and PLC were cultured and irradiated with photons or carbon ions at the Heidelberg Ion Beam Therapy Center using the raster-scanning method. For combination experiments, cell lines were first treated with Temsirolimus or GEM before irradiation. Cytotoxicity was measured by a clonogenic survival assay. The evaluation of the experiments and the obtained survival curves were based on the concept of additivity defined by Steel and Peckham. RESULTS: The results for the combination of carbon ions and both tested systemic substances TEM and GEM showed independent toxicities in all four cell lines. Supra-additive effects were observed in PLC cells for photon irradiation combined either with TEM or GEM and in HuH7 cells for the combination of photons with TEM. CONCLUSION: Addition of targeted therapy substances Temsirolimus and GEM to photon irradiation showed additive cytotoxicity in HCC cell lines, whereas independent toxicities where reached by the combination of carbon ions to these substances. It can be assumed that combining 12C with systemic substances only has independent effects because heavy ions cause direct damage because of their high-LET character resulting in complex and clustered double-strand breaks. Nonetheless, further investigations are warranted in order to determine whether addition of systemic therapy allows a reduction of radiation doses in combination therapy. This could possibly lead to better responses and tolerances in patients with HCC.

15.
Oncotarget ; 7(35): 56676-56689, 2016 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-27494855

RESUMO

The growing number of particle therapy facilities worldwide landmarks a novel era of precision oncology. Implementation of robust biophysical readouts is urgently needed to assess the efficacy of different radiation qualities. This is the first report on biophysical evaluation of Monte Carlo simulated predictive models of prescribed dose for four particle qualities i.e., proton, helium-, carbon- or oxygen ions using raster-scanning technology and clinical therapy settings at HIT. A high level of agreement was found between the in silico simulations, the physical dosimetry and the clonogenic tumor cell survival. The cell fluorescence ion track hybrid detector (Cell-Fit-HD) technology was employed to detect particle traverse per cell nucleus. Across a panel of radiobiological surrogates studied such as late ROS accumulation and apoptosis (caspase 3/7 activation), the relative biological effectiveness (RBE) chiefly correlated with the radiation species-specific spatio-temporal pattern of DNA double strand break (DSB) formation and repair kinetic. The size and the number of residual nuclear γ-H2AX foci increased as a function of linear energy transfer (LET) and RBE, reminiscent of enhanced DNA-damage complexity and accumulation of non-repairable DSB. These data confirm the high relevance of complex DSB formation as a central determinant of cell fate and reliable biological surrogates for cell survival/ RBE. The multi-scale simulation, physical and radiobiological characterization of novel clinical quality beams presented here constitutes a first step towards development of high precision biologically individualized radiotherapy.


Assuntos
Carbono/uso terapêutico , Radioterapia com Íons Pesados/métodos , Hélio/uso terapêutico , Neoplasias/radioterapia , Oxigênio/uso terapêutico , Terapia com Prótons/métodos , Células A549 , Linhagem da Célula , Sobrevivência Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Histonas/metabolismo , Humanos , Transferência Linear de Energia , Método de Monte Carlo , Radiometria , Eficiência Biológica Relativa , Reprodutibilidade dos Testes , Software
16.
Int J Radiat Oncol Biol Phys ; 95(1): 435-43, 2016 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-27084659

RESUMO

PURPOSE: The purpose of this study was to compare safety and feasibility of proton therapy with that of carbon ion therapy in hypofractionated raster-scanned irradiation of the prostate, in a prospective randomized phase 2 trial. METHODS AND MATERIALS: In this trial, 92 patients with localized prostate cancer were enrolled. Patients were randomized to receive either proton therapy (arm A) or carbon ion therapy (arm B) and treated with a total dose of 66 Gy(relative biological effectiveness [RBE]) administered in 20 fractions (single dose of 3.3 Gy[RBE]). Patients were stratified by the use of antihormone therapy. Primary endpoint was the combined assessment of safety and feasibility. Secondary endpoints were specific toxicities, prostate-specific antigen progression-free survival (PFS), overall survival (OS), and quality of life (QoL). RESULTS: Ninety-one patients completed therapy and have had a median follow-up of 22.3 months. Among acute genitourinary toxicities, grade 1 cystitis rates were 34.1% (39.1% in A; 28.9% in B) and 17.6% grade 2 (21.7% in A; 13.3% in B). Seven patients (8%) required urinary catheterization during treatment due to urinary retention, 5 of whom were in arm A. Regarding acute gastrointestinal toxicities, 2 patients treated with protons developed grade 3 rectal fistulas. Grade 1 radiation proctitis occurred in 12.1% (13.0% in A; 11.1% in B) and grade 2 in 5.5% (8.7% in A; 2.2% in B). No statistically significant differences in toxicity profiles between arms were found. Reduced QoL was evident mainly in fatigue, pain, and urinary symptoms during therapy and 6 weeks thereafter. All European Organization for Research and Treatment of Cancer QLQ-C30 and -PR25 scores improved during follow-up. CONCLUSIONS: Hypofractionated irradiation using either carbon ions or protons results in comparable acute toxicities and QoL parameters. We found that hypofractionated particle irradiation is feasible and may be safe. Due to the occurrence of gel in the rectal wall and the consecutive occurrence of 2 rectal fistulas, we stopped using the insertion of spacer gel. Longer follow-up is necessary for evaluation of PFS and OS. (Ion Prostate Irradiation (IPI); NCT01641185; ClinicalTrials.gov.).


Assuntos
Radioterapia com Íons Pesados/efeitos adversos , Neoplasias da Próstata/radioterapia , Terapia com Prótons/efeitos adversos , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Cistite/etiologia , Cistite/patologia , Intervalo Livre de Doença , Fadiga/etiologia , Estudos de Viabilidade , Seguimentos , Radioterapia com Íons Pesados/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Terapia com Prótons/métodos , Hipofracionamento da Dose de Radiação , Lesões por Radiação/prevenção & controle , Reto/efeitos da radiação , Eficiência Biológica Relativa , Segurança , Fatores de Tempo , Cateterismo Urinário/estatística & dados numéricos , Retenção Urinária/terapia
17.
J Radiat Res ; 57(2): 110-4, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26747201

RESUMO

Densely ionizing charged particle irradiation offers physical as well as biological advantages compared with photon irradiation. Radiobiological data for the combination of such particle irradiation (i.e. therapeutic carbon ions) with commonly used chemotherapeutics are still limited. Recent in vitro results indicate a general prevalence of additive cytotoxic effects in combined treatments, but an extension of established multimodal treatment regimens with photons to the inclusion of particle therapy needs to evaluate possible peculiarities of using high linear energy transfer (LET) radiation. The present study investigates the effect of combined radiochemotherapy using gemcitabine and high-LET irradiation with therapeutic carbon ions. In particular, the earlier observation of S-phase specific radiosensitization with photon irradiation should be evaluated with carbon ions. In the absence of the drug gemcitabine, carbon ion irradiation produced the typical survival behavior seen with X-rays-increased relative biological efficiency, and depletion of the survival curve's shoulder. By means of serum deprivation and subsequent replenishment, ∼70% S-phase content of the cell population was achieved, and such preparations showed radioresistance in both treatment arms-,photon and carbon ion irradiation. Combined modality treatment with gemcitabine caused significant reduction of clonogenic survival especially for the S-phase cells. WIDR cells exhibited S-phase-specific radioresistance with high-LET irradiation, although this was less pronounced than for X-ray exposure. The combined treatment with therapeutic carbon ions and gemcitabine caused the resistance phenomenon to disappear phenotypically.


Assuntos
Desoxicitidina/análogos & derivados , Radioterapia com Íons Pesados , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , Fase S/efeitos dos fármacos , Fase S/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Desoxicitidina/farmacologia , Humanos , Ensaio Tumoral de Célula-Tronco
18.
Radiother Oncol ; 118(2): 272-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26164774

RESUMO

PURPOSE: Locoregional control (LC) in malignant salivary gland tumors is dose-dependent, initial results with particle therapy were promising. We report our experience with raster-scanned, intensity-controlled carbon ion therapy (C12) and IMRT in 309 patients with pathologically confirmed adenoid cystic carcinoma (ACC) of the head and neck. PATIENTS AND METHODS: Treatment records of patients treated with C12 between 08/1998 and 05/2013 were evaluated regarding tumor stage, treatment, toxicity (CTCAE v3), LC, progression-free survival (PFS) and overall survival (OS). Response assessment was carried out according to RECIST1.1. RESULTS: Tumor stages were mostly advanced (T4a/b: 60%, macroscopic disease: 71%), most common sites of origin were the paranasal sinus (37%). At a median follow-up at 33.9 months, LC, PFS, and OS at 3 and 5 year estimates are 83.7%/58.5%, 67.8%/56.1%, and 88.9%/74.6%. LC correlates with T-stage but neither nodal stage, age, relapse state, nor margin status. RECIST did not correlate with LC or survival rates. CONCLUSION: IMRT plus C12 boost results in good control and survival rates at moderate toxicity. Margin status did not correlate with LC in T4 tumors, extensive and potentially mutilating surgical procedures may have to be re-evaluated. RECIST assessment did not correlate with either LC or survival rates; potentially more meaningful radiological parameters need to be developed.


Assuntos
Carcinoma Adenoide Cístico/radioterapia , Radioterapia com Íons Pesados/métodos , Neoplasias das Glândulas Salivares/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
19.
Int J Radiat Oncol Biol Phys ; 93(1): 37-46, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26279022

RESUMO

PURPOSE: To investigate the effect of intensity modulated radiation therapy (IMRT) and dose-escalated carbon ion (C12) therapy in adenoid cystic carcinoma (ACC) and other malignant salivary gland tumors (MSGTs) of the head and neck. PATIENTS AND METHODS: COSMIC (combined treatment of malignant salivary gland tumors with intensity modulated radiation therapy and carbon ions) is a prospective phase 2 trial of 24 Gy(RBE) C12 followed by 50 Gy IMRT in patients with pathologically confirmed MSGT. The primary endpoint is mucositis Common Terminology Criteria grade 3; the secondary endpoints are locoregional control (LC), progression-free survival (PFS), overall survival (OS), and toxicity. Toxicity was scored according to the Common Terminology Criteria for Adverse Events version 3; treatment response was scored according to Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: Between July 2010 and August 2011, 54 patients were accrued, and 53 were available for evaluation. The median follow-up time was 42 months; patients with microscopically incomplete resections (R1, n = 20), gross residual disease (R2, n = 17), and inoperable disease (n = 16) were included. Eighty-nine percent of patients had ACC, and 57% had T4 tumors. The most common primary sites were paranasal sinus (34%), submandibular gland, and palate. At the completion of radiation therapy, 26% of patients experienced grade 3 mucositis, and 20 patients reported adverse events of the ear (38%). The most common observed late effects were grade 1 xerostomia (49%), hearing impairment (25%, 2% ipsilateral hearing loss), and adverse events of the eye (20%), but no visual impairment or loss of vision. Grade 1 central nervous system necrosis occurred in 6%, and 1 grade 4 ICA hemorrhage without neurologic sequelae. The best response was 54% (complete response/partial remission). At 3 years, the LC, PFS, and OS were 81.9%, 57.9%, and 78.4%, respectively. No difference was found regarding resection status. The most common site of failure was distant (55%). Local relapse was predominantly in field (79%). CONCLUSION: Treatment was tolerated, with moderate acute and late toxicity. The LC at 3 years was promising. No significant difference could be shown regarding resection status; hence, extensive and mutilating surgical procedures should be rediscussed. Further dose escalation may be limited in view of potential vascular adverse events.


Assuntos
Radioisótopos de Carbono/uso terapêutico , Carcinoma Adenoide Cístico/radioterapia , Radioterapia de Intensidade Modulada/métodos , Neoplasias das Glândulas Salivares/radioterapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Órgãos em Risco , Estudos Prospectivos , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos
20.
Cancer ; 121(17): 3001-9, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26043145

RESUMO

BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated.


Assuntos
Carcinoma Adenoide Cístico/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Carcinoma Adenoide Cístico/mortalidade , Intervalo Livre de Doença , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Radioterapia de Intensidade Modulada , Resultado do Tratamento , Adulto Jovem
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