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1.
Front Oncol ; 14: 1353813, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38887236

RESUMO

Objective: This multicenter study aimed to retrospectively evaluate the impact of high boost simultaneous integrated boost (SIB) to pathologic lymph nodes compared to Sequential boost (Seq) in patients with locally advanced cervical cancer (LACC). Materials and methods: 97 patients with pelvic and/or para-aortic (PAo) node-positive LACC treated by definitive chemoradiation were included. Two groups were analyzed: Sequential boost group and simultaneous integrated boost (SIB) group. Endpoints were Distant Recurrence Free Survival (DRFS), Recurrence Free Survival (RFS), Overall Survival (OS), locoregional pelvic and PAo control and toxicities. Results: 3-years DRFS in SIB and Seq groups was 65% and 31% respectively (log-rank p < 0.001). 3-years RFS was 58% and 26% respectively (log-rank p = 0.009). DRFS prognostic factors in multivariable analysis were SIB, PAo involvement and maximum pelvic node diameter ≥ 2cm. Adenocarcinoma histology and absence of brachytherapy tended to be prognostic factors. SIB provided the best pelvic control at first imaging with 97%. There was no significant difference in terms of toxicities between groups. Conclusions: Nodal SIB seems to be unavoidable in the treatment of node-positive LACC. It provides the best DRFS, RFS and pelvic control without additional toxicity, with a shortened treatment duration.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38462014

RESUMO

PURPOSE: Novel radiation therapy approaches have increased the therapeutic efficacy for malignant brain tumors over the past decades, but the balance between therapeutic gain and radiotoxicity remains a medical hardship. Synchrotron microbeam radiation therapy, an innovative technique, deposes extremely high (peak) doses in micron-wide, parallel microbeam paths, whereas the diffusing interbeam (valley) doses lie in the range of conventional radiation therapy doses. In this study, we evaluated normal tissue toxicity of whole-brain microbeam irradiation (MBI) versus that of a conventional hospital broad beam (hBB). METHODS AND MATERIALS: Normal Fischer rats (n = 6-7/group) were irradiated with one of the two modalities, exposing the entire brain to MBI valley/peak doses of 0/0, 5/200, 10/400, 13/520, 17/680, or 25/1000 Gy or to hBB doses of 7, 10, 13, 17, or 25 Gy. Two additional groups of rats received an MBI valley dose of 10 Gy coupled with an hBB dose of 7 or 15 Gy (groups MBI17* and MBI25*). Behavioral parameters were evaluated for 10 months after irradiation combined with veterinary observations. RESULTS: MBI peak doses of ≥680 Gy caused acute toxicity and death. Animals exposed to hBB or MBI dose-dependently gained less weight than controls; rats in the hBB25 and MBI25* groups died within 6 months after irradiation. Increasing doses of MBI caused hyperactivity but no other detectable behavioral alterations in our tests. Importantly, no health concerns were seen up to an MBI valley dose of 17 Gy. CONCLUSIONS: While acute toxicity of microbeam exposures depends on very high peak doses, late toxicity mainly relates to delivery of high MBI valley doses. MBI seems to have a low impact on normal rat behavior, but further tests are warranted to fully explore this hypothesis. However, high peak and valley doses are well tolerated from a veterinary point of view. This normal tissue tolerance to whole-brain, high-dose MBI reveals a promising avenue for microbeam radiation therapy, that is, therapeutic applications of microbeams that are poised for translation to a clinical environment.

3.
Cancers (Basel) ; 14(12)2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35740495

RESUMO

Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

4.
BMC Cancer ; 22(1): 575, 2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35606739

RESUMO

BACKGROUND: Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy. METHODS: The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study. DISCUSSION: So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02838602 . Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.


Assuntos
Carcinoma Adenoide Cístico , Radioterapia com Íons Pesados , Terapia com Prótons , Sarcoma , Neoplasias de Tecidos Moles , Carbono/efeitos adversos , Radioterapia com Íons Pesados/efeitos adversos , Humanos , Íons/uso terapêutico , Fótons/efeitos adversos , Estudos Prospectivos , Terapia com Prótons/efeitos adversos , Prótons , Qualidade de Vida , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico
5.
Int J Radiat Oncol Biol Phys ; 113(5): 967-973, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35483539

RESUMO

PURPOSE: The high potential of microbeam radiation therapy (MRT) in improving tumor control while reducing side effects has been shown by numerous preclinical studies. MRT offers a widened therapeutic window by using the periodical spatial fractionation of synchrotron generated x-rays into an array of intense parallel microbeams. MRT now enters a clinical transfer phase. As proof of principle and cornerstone for the safe clinical transfer of MRT, we conducted a "first in dog" trial under clinical conditions. In this report, we evaluated whether a 3-dimensional conformal MRT can be safely delivered as exclusive radiosurgical treatment in animal patients METHODS AND MATERIALS: We irradiated a 17.5-kg French bulldog for a spontaneous brain tumor (glioma suspected on magnetic resonance imaging) with conformal high-dose-rate microbeam arrays (50-µm-wide microbeams, replicated with a pitch of 400 µm) of synchrotron-generated x-rays. The dose prescription adjusted a minimal cumulated valley dose of 2.8 Gy to the plnning target volume (PTV) (cinical target volume (CTV)+ 1 mm). Thus, each beam delivered 20 to 25 Gy to the target as peak doses, and ∼1 Gy as valley doses RESULTS: The treatment was successfully delivered. Clinical follow-up over 3 months showed a significant improvement of the dog's quality of life: the symptoms disappeared. Magnetic resonance imaging, performed 3 months after irradiation, revealed reduction in tumor size (-87.4%) and mass effect with normalization of the left lateral ventricle. CONCLUSIONS: To our knowledge, this neuro-oncologic veterinary trial is the first 3-dimensional conformal synchrotron x-ray MRT treatment of a spontaneous intracranial tumor in a large animal. It is an essential last step toward the clinical transfer of MRT in the near future to demonstrate the feasibility and safety of treating deep-seated tumors using synchrotron-generated microbeams.


Assuntos
Neoplasias Encefálicas , Glioma , Radiocirurgia , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/veterinária , Cães , Glioma/diagnóstico por imagem , Glioma/patologia , Glioma/radioterapia , Qualidade de Vida , Radiocirurgia/métodos , Síncrotrons
6.
Mol Neurobiol ; 59(1): 556-573, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34727321

RESUMO

Neurofibromatosis type 1 (NF1) is a disease characterized by high occurrence of benign and malignant brain tumours and caused by mutations of the neurofibromin protein. While there is an increasing evidence that NF1 is associated with radiosensitivity and radiosusceptibility, few studies have dealt with the molecular and cellular radiation response of cells from individuals with NF1. Here, we examined the ATM-dependent signalling and repair pathways of the DNA double-strand breaks (DSB), the key-damage induced by ionizing radiation, in skin fibroblast cell lines from 43 individuals with NF1. Ten minutes after X-rays irradiation, quiescent NF1 fibroblasts showed abnormally low rate of recognized DSB reflected by a low yield of nuclear foci formed by phosphorylated H2AX histones. Irradiated NF1 fibroblasts also presented a delayed radiation-induced nucleoshuttling of the ATM kinase (RIANS), potentially due to a specific binding of ATM to the mutated neurofibromin in cytoplasm. Lastly, NF1 fibroblasts showed abnormally high MRE11 nuclease activity suggesting a high genomic instability after irradiation. A combination of bisphosphonates and statins complemented these impairments by accelerating the RIANS, increasing the yield of recognized DSB and reducing genomic instability. Data from NF1 fibroblasts exposed to radiation in radiotherapy and CT scan conditions confirmed that NF1 belongs to the group of syndromes associated with radiosensitivity and radiosusceptibility.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sobrevivência Celular/efeitos da radiação , Reparo do DNA/efeitos da radiação , Difosfonatos/farmacologia , Fibroblastos/efeitos da radiação , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neurofibromatose 1/radioterapia , Radiação Ionizante , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Neurofibromatose 1/metabolismo
7.
Quant Imaging Med Surg ; 11(8): 3481-3493, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34341725

RESUMO

BACKGROUND: Imaging, in radiotherapy, has become a routine tool for repositioning of the target volume at each session. The repositioning precision, currently infracentimetric, evolves along with the irradiation techniques. This retrospective study aimed to identify practices and doses resulting from the use of high energy planar imaging (portal imaging) in daily practice. METHODS: A retrospective survey of portal images (PIs) was carried out over 10 years for 2,403 patients and for three linacs (1 Elekta SLi, 2 Varian Clinac) for postoperative mammary irradiations. Images were taken using a standardized number of monitor units (MU) for all patients. Due to the variable sensitivities of the detectors and the possibility of adjustment of the detector-patient distance, the number of MU were 3; 2 and 1 respectively, for Elekta SLi®, Clinac 600® and Clinac 2100®. Then, a representative cumulated dose was calculated in simplified reference conditions (5 cm depth, beam of 10 cm × 10 cm, 6 MV), considering the total number of images taken during the whole treatment course. The consistency between the representative doses and the actual absorbed doses received by the patients was verified by simulating a series of typical cases with the treatment plan dose calculation system. RESULTS: The delivered doses differ significantly between the three linacs. The mean representative dose values by complete treatment were 0.695; 0.241 and 0.216 Gy, respectively, for SLi, Clinac 600 and Clinac 2100. However, 15 patients were exposed to a dose >2 Gy with a maximum dose of 5.05 Gy. The simulated doses were very similar to the representative doses. CONCLUSIONS: A significant dose delivery was highlighted by this study. These representative doses are presently communicated weekly to the radiation oncologist for the radiation protection of their patients. Moreover, they should be taken into account in a possible study of long-term stochastic risks.

8.
Front Oncol ; 11: 673886, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211847

RESUMO

PURPOSE: Proton therapy (PT) can be a good option to achieve tumor control while reducing the probability of radiation induced toxicities compared to X-ray-based radiotherapy. However, there are still uncertainties about the effects of PT on the organs in direct contact with the irradiated volume. The aim of this prospective series was to report 6-month follow-up of clinical and functional optic neuropathy rates of patients treated by proton therapy using a standardized comprehensive optic examination. METHODS AND MATERIALS: Standardized ophthalmological examinations were performed to analyze subclinical anomalies in a systematic way before treatment and 6 months after the end of proton therapy with: Automatic visual field, Visual evoked potential (VEP) and optic coherence of tomography (OCT). RESULTS: From October 2018 to July 2020 we analyzed 81 eyes. No significant differences were found in the analysis of the clinical examination of visual functions by the radiation oncologist. However, considering VEP, the impairment was statistically significant for both fibers explored at 30'angle (p:0.007) and 60'angle (p <0.001). In patients with toxicity, the distance of the target volume from the optical pathways was more important with a p-value for 30'VEP at 0.035 and for 60'VEP at 0.039. CONCLUSIONS: These results confirm uncertainties concerning relative biological effectiveness of proton therapy, linear energy transfer appears to be more inhomogeneous especially in areas close to the target volumes. The follow-up of patients after proton therapy is not an easy process to set up but it is necessary to improve our knowledges about the biological effects of proton therapy in real life. Our study which will continue during the coming years, suggests that follow-up with in-depth examinations such as VEP as a biomarker could improve the detection of early abnormalities.

9.
Cancer Radiother ; 25(6-7): 545-549, 2021 Oct.
Artigo em Francês | MEDLINE | ID: mdl-34175224

RESUMO

Considering intracranial tumours, only few indications of protontherapy, such as chordoma, chondrosarcoma or uveal melanoma, are uniformly approved in the world. Other indications, excluding paediatric pathologies, are still debated. The aim of this article is to describe the rationale for the use of protonbeam irradiation for meningioma, pituitary adenoma, craniopharyngioma, paraganglioma, glioma, and schwannoma, and to inform the radiation oncologists if prospective studies or randomized studies are opened for inclusions. This article deals only with indications for adults.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Neoplasias Hipofisárias/radioterapia , Adenoma/radioterapia , Adulto , Cordoma/radioterapia , Craniofaringioma/radioterapia , Glioma/radioterapia , Humanos , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Neurilemoma/radioterapia , Paraganglioma/radioterapia , Estudos Prospectivos , Dosagem Radioterapêutica , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Radiother Oncol ; 160: 159-165, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961915

RESUMO

BACKGROUND AND PURPOSE: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy. MATERIALS AND METHODS: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03. RESULTS: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T1 MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect. CONCLUSION: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy.


Assuntos
Neoplasias Encefálicas , Nanopartículas , Radiossensibilizantes , Neoplasias Encefálicas/radioterapia , Humanos , Medicina de Precisão , Qualidade de Vida
11.
Cancers (Basel) ; 13(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668110

RESUMO

Delivery of high-radiation doses to brain tumors via multiple arrays of synchrotron X-ray microbeams permits huge therapeutic advantages. Brain tumor (9LGS)-bearing and normal rats were irradiated using a conventional, homogeneous Broad Beam (BB), or Microbeam Radiation Therapy (MRT), then studied by behavioral tests, MRI, and histopathology. A valley dose of 10 Gy deposited between microbeams, delivered by a single port, improved tumor control and median survival time of tumor-bearing rats better than a BB isodose. An increased number of ports and an accumulated valley dose maintained at 10 Gy delayed tumor growth and improved survival. Histopathologically, cell death, vascular damage, and inflammatory response increased in tumors. At identical valley isodose, each additional MRT port extended survival, resulting in an exponential correlation between port numbers and animal lifespan (r2 = 0.9928). A 10 Gy valley dose, in MRT mode, delivered through 5 ports, achieved the same survival as a 25 Gy BB irradiation because of tumor dose hot spots created by intersecting microbeams. Conversely, normal tissue damage remained minimal in all the single converging extratumoral arrays. Multiport MRT reached exceptional ~2.5-fold biological equivalent tumor doses. The unique normal tissue sparing and therapeutic index are eminent prerequisites for clinical translation.

12.
J Surg Oncol ; 123(1): 299-310, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33098678

RESUMO

BACKGROUND: Rate of abdominoperineal resection (APR) varies from countries and surgeons. Surgical impact of preoperative treatment for ultra-low rectal carcinoma (ULRC) initially indicated for APR is debated. We report the 10-year oncological results from a prospective controlled trial (GRECCAR 1) which evaluate the sphincter saving surgery (SSR). METHODS: ULRC indicated for APR were included (n = 207). Randomization was between high-dose radiation (HDR, 45 + 18 Gy) and radiochemotherapy (RCT, 45 Gy + 5FU infusion). Surgical decision was based on tumour volume regression at surgery. SSR technique was standardized as mucosectomy (M) or partial (PISR)/complete (CISR) intersphincteric resection. RESULTS: Overall SSR rate was 85% (72% ISR), postoperative morbidity 27%, with no mortality. There were no significant differences between the HDR and RCT groups: 10-year overall survival (OS10) 70.1% versus 69.4%, respectively, 10.2% local recurrence (9.2%/14.5%) and 27.6% metastases (32.4%/27.7%). OS and disease-free survival were significantly longer for SSR (72.2% and 60.1%, respectively) versus APR (54.7% and 38.3%). No difference in OS10 between surgical approaches (M 78.9%, PISR 75.5%, CISR 65.5%) or tumour location (low 64.8%, ultralow 76.7%). CONCLUSION: GRECCAR 1 demonstrates the feasibility of safely changing an initial APR indication into an SSR procedure according to the preoperative treatment tumour response. Long-term oncologic follow-up validates this attitude.


Assuntos
Adenocarcinoma/cirurgia , Canal Anal/cirurgia , Tratamentos com Preservação do Órgão/métodos , Protectomia/métodos , Neoplasias Retais/cirurgia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Canal Anal/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Neoplasias Retais/patologia
13.
J Neurooncol ; 149(2): 193-208, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32809095

RESUMO

BACKGROUND: The purpose of this review is to summarize our own experimental studies carried out over a 13-year period of time using the F98 rat glioma as model for high grade gliomas. We evaluated a binary chemo-radiotherapeutic modality that combines either cisplatin (CDDP) or carboplatin, administered intracerebrally (i.c.) by means of convection-enhanced delivery (CED) or osmotic pumps, in combination with either synchrotron or conventional X-irradiation. METHODS: F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Approximately 14 days later, either CDDP or carboplatin was administered i.c. by CED, followed 24 h later by radiotherapy using either a synchrotron or, subsequently, megavoltage linear accelerators (LINAC). RESULTS: CDDP was administered at a dose of 3 µg in 5 µL, followed 24 h later with an irradiation dose of 15 Gy or carboplatin at a dose of 20 µg in 10 µL, followed 24 h later with 3 fractions of 8 Gy each, at the source at the European Synchrotron Radiation Facility (ESRF). This resulted in a median survival time (MeST) > 180 days with 33% long term survivors (LTS) for CDDP and a MeST > 60 days with 8 to 22% LTS, for carboplatin. Subsequently it became apparent that comparable survival data could be obtained with megavoltage X-irradiation using a LINAC source. The best survival data were obtained with a dose of 72 µg of carboplatin administered by means of Alzet® osmotic pumps over 7 days. This resulted in a MeST of > 180 days, with 55% LTS. Histopathologic examination of all the brains of the surviving rats revealed no residual tumor cells or evidence of significant radiation related effects. CONCLUSIONS: The results obtained using this combination therapy has, to the best of our knowledge, yielded the most promising survival data ever reported using the F98 glioma model.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Sistemas de Liberação de Medicamentos , Glioma/terapia , Animais , Neoplasias Encefálicas/patologia , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Convecção , Glioma/patologia , Infusões Intralesionais , Ratos
14.
Sci Adv ; 6(29): eaay5279, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32832613

RESUMO

The use of radiosensitizing nanoparticles with both imaging and therapeutic properties on the same nano-object is regarded as a major and promising approach to improve the effectiveness of radiotherapy. Here, we report the MRI findings of a phase 1 clinical trial with a single intravenous administration of Gd-based AGuIX nanoparticles, conducted in 15 patients with four types of brain metastases (melanoma, lung, colon, and breast). The nanoparticles were found to accumulate and to increase image contrast in all types of brain metastases with MRI enhancements equivalent to that of a clinically used contrast agent. The presence of nanoparticles in metastases was monitored and quantified with MRI and was noticed up to 1 week after their administration. To take advantage of the radiosensitizing property of the nanoparticles, patients underwent radiotherapy sessions following their administration. This protocol has been extended to a multicentric phase 2 clinical trial including 100 patients.

15.
Int J Radiat Oncol Biol Phys ; 107(2): 360-369, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088292

RESUMO

PURPOSE: Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly collimated synchrotron beam into arrays of parallel microbeams depositing several hundred grays. It appears relevant to combine MRT with a conventional treatment course, preparing a treatment scheme for future patients in clinical trials. The efficiency of MRT delivered after several broad-beam (BB) fractions to palliate F98 brain tumors in rats in comparison with BB fractions alone was evaluated in this study. METHODS AND MATERIALS: Rats bearing 106 F98 cells implanted in the caudate nucleus were irradiated by 5 fractions in BB mode (3 × 6 Gy + 2 × 8 Gy BB) or by 2 boost fractions in MRT mode to a total of 5 fractions (3 × 6 Gy BB + MRT 2 × 8 Gy valley dose; peak dose 181 Gy [50/200 µm]). Tumor growth was evaluated in vivo by magnetic resonance imaging follow-up at T-1, T7, T12, T15, T20, and T25 days after radiation therapy and by histology and flow cytometry. RESULTS: MRT-boosted tumors displayed lower cell density and cell proliferation compared with BB-irradiated tumors. The MRT boost completely stopped tumor growth during ∼4 weeks and led to a significant increase in median survival time, whereas tumors treated with BB alone recurred within a few days after the last radiation fraction. CONCLUSIONS: The first evidence is presented that MRT, delivered as a boost of conventionally fractionated irradiation by orthovoltage broad x-ray beams, is feasible and more efficient than conventional radiation therapy alone.


Assuntos
Neoplasias Encefálicas/radioterapia , Fracionamento da Dose de Radiação , Glioblastoma/radioterapia , Glioma/radioterapia , Síncrotrons , Terapia por Raios X/instrumentação , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Ciclo Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Wistar , Carga Tumoral/efeitos da radiação
16.
Int J Mol Sci ; 21(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878191

RESUMO

The resistance of cancer cells to radiotherapy is a major issue in the curative treatment of cancer patients. This resistance can be intrinsic or acquired after irradiation and has various definitions, depending on the endpoint that is chosen in assessing the response to radiation. This phenomenon might be strengthened by the radiosensitivity of surrounding healthy tissues. Sensitive organs near the tumor that is to be treated can be affected by direct irradiation or experience nontargeted reactions, leading to early or late effects that disrupt the quality of life of patients. For several decades, new modalities of irradiation that involve accelerated particles have been available, such as proton therapy and carbon therapy, raising the possibility of specifically targeting the tumor volume. The goal of this review is to examine the up-to-date radiobiological and clinical aspects of hadrontherapy, a discipline that is maturing, with promising applications. We first describe the physical and biological advantages of particles and their application in cancer treatment. The contribution of the microenvironment and surrounding healthy tissues to tumor radioresistance is then discussed, in relation to imaging and accurate visualization of potentially resistant hypoxic areas using dedicated markers, to identify patients and tumors that could benefit from hadrontherapy over conventional irradiation. Finally, we consider combined treatment strategies to improve the particle therapy of radioresistant cancers.


Assuntos
Neoplasias/radioterapia , Radioterapia/métodos , Humanos , Hipóxia , Terapia com Prótons
17.
Sci Rep ; 9(1): 17082, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745153

RESUMO

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.


Assuntos
Comportamento Animal/efeitos da radiação , Encéfalo/patologia , Núcleo Caudado/patologia , Irradiação Craniana/efeitos adversos , Comportamento Alimentar/efeitos da radiação , Locomoção/efeitos da radiação , Lesões por Radiação/patologia , Animais , Encéfalo/efeitos da radiação , Núcleo Caudado/efeitos da radiação , Masculino , Lesões por Radiação/etiologia , Suínos , Porco Miniatura , Síncrotrons
18.
Phys Med ; 65: 227-237, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574356

RESUMO

Microbeam radiation therapy (MRT) uses synchrotron arrays of X-ray microbeams to take advantage of the spatial fractionation effect for normal tissue sparing. In this study, radiochromic film dosimetry was performed for a treatment where MRT is introduced as a dose boost in a hypofractionated stereotactic radiotherapy (SRT) scheme. The isocenter dose was measured using an ionization chamber and two dimensional dose distributions were determined using radiochromic films. To compare the measured dose distribution to the MRT treatment plan, peak and valley were displayed in separate dosemaps. The measured and computed isocenter doses were compared and a two-dimensional 2%/2 mm normalized γ-index analysis with a 90% passing rate criterion was computed. For SRT, a difference of 2.6% was observed in the dose at the isocenter from the treatment plan and film measurement, with a passing rate of 96% for the γ-index analysis. For MRT, peak and valley doses differences of 25.6% and 8.2% were observed, respectively but passing rates of 96% and 90% respectively were obtained from the normalized γ-index maps. The differences in isocenter doses measured in MRT should be further investigated. We present the methodology of patient specific quality assurance (QA) for studying MRT dose distributions and discuss ideas to improve absolute dosimetry. This patient specific QA will be used for large animal trials quality assurance where MRT will be administered as a dose boost in conventional SRT. The observed remaining discrepancies should be studied against approximations in the TPS phantom materials, beams characteristics or film read-out procedures.


Assuntos
Dosimetria Fotográfica/métodos , Radioterapia/métodos , Neoplasias Encefálicas/radioterapia , Fracionamento da Dose de Radiação , Humanos , Imagens de Fantasmas , Radiometria/métodos , Dosagem Radioterapêutica , Síncrotrons , Raios X
19.
Clin Colorectal Cancer ; 18(3): 200-208.e1, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31311761

RESUMO

BACKGROUND: Recurrence and distant metastases remain a significant issue in locally advanced rectal cancer (LARC). Several multimodal strategies are assessed in clinical trials. PATIENTS AND METHODS: Patients with mid/low magnetic resonance imaging-defined high-risk LARC were randomized to arm A (12-week bevacizumab + FOLFOX-4 then bevacizumab-5-fluorouracil [5-FU]-radiotherapy [RT] before total mesorectal excision [TME]) or arm B (bevacizumab-5-FU-RT then TME). Long-term efficacy and safety up to 5 years' follow-up are reported. No comparison between arms was planned. RESULTS: Overall, 91 patients (46 in arm A and 45 in arm B) were included. Main results have been presented previously. During the late follow-up period (> 4 weeks after surgery), 4 patients (8.7%) in arm A and 4 (8.9%) in arm B experienced grade 3/4 adverse events related to bevacizumab; the most frequent were 2 anastomotic fistulas (both in arm A) and abscesses (1 in arm A and 2 in arm B). At 5 years' follow-up, 9 (19.6%) and 11 (24.4%) patients in arms A and B developed a fistula in the year after surgery, and 2 (4.3%) in arm A at > 1 year after surgery. Most resolved before study end. Five-year disease-free survival was 70% and 64.3% in arms A and B, respectively. Five-year overall survival was 90.5% (95% confidence interval, 76.7, 96.3) in arm A and 72.7% (95% confidence interval, 56.0, 83.9) in arm B. CONCLUSION: Neoadjuvant bevacizumab + FOLFOX-4 may have the potential to increase survival outcomes when followed by bevacizumab-5-FU-RT and TME in LARC. Bevacizumab-5-FU-RT then TME was associated with a higher-than-projected rate of anastomotic fistulas. Further research of neoadjuvant strategies in LARC is encouraged.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Retais/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Adolescente , Adulto , Idoso , Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Quimiorradioterapia Adjuvante , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Leucovorina/administração & dosagem , Metástase Linfática , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Oxaliplatina/administração & dosagem , Neoplasias Retais/patologia , Neoplasias Retais/radioterapia , Neoplasias Retais/cirurgia , Taxa de Sobrevida , Adulto Jovem
20.
Radiother Oncol ; 139: 56-61, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31307824

RESUMO

This paper reviews the current state of the art of an emerging form of radiosurgery dedicated to brain tumour treatment and which operates at very high dose rate (kGy·s-1). Microbeam Radiation Therapy uses synchrotron-generated X-rays which triggered normal tissue sparing partially mediated by FLASH effect.


Assuntos
Neoplasias Encefálicas/radioterapia , Radiocirurgia/métodos , Síncrotrons , Animais , Neoplasias Encefálicas/irrigação sanguínea , Protocolos Clínicos , Modelos Animais de Doenças , Humanos , Raios X
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