Experimental optimisation of the X-ray energy in microbeam radiation therapy

Microbeam radiation therapy has demonstrated superior normal tissue sparing properties compared to broadbeam radiation fields. The ratio of the microbeam peak dose to the valley dose (PVDR), which is dependent on the X-ray energy/spectrum and geometry, should be maximised for an optimal therapeutic ratio. Simulation studies in the literature report the optimal energy for MRT based on the PVDR. However, most of these studies have considered different microbeam geometries to that at the Imaging and Medical Beamline (50 μm beam width with a spacing of 400 μm). We present the first fully experimental investigation of the energy dependence of PVDR and microbeam penumbra. Using monochromatic X-ray energies in the range 40–120 keV the PVDR was shown to increase with increasing energy up to 100 keV before plateauing. PVDRs measured for pink beams were consistently higher than those for monochromatic energies similar or equivalent to the average energy of the spectrum. The highest PVDR was found for a pink beam average energy of 124 keV. Conversely, the microbeam penumbra decreased with increasing energy before plateauing for energies above 90 keV. The effect of bone on the PVDR was investigated at energies 60, 95 and 120 keV. At depths greater than 20 mm beyond the bone/water interface there was almost no effect on the PVDR. In conclusion, the optimal energy range for MRT at IMBL is 90–120 keV, however when considering the IMBL flux at different energies, a spectrum with 95 keV weighted average energy was found to be the best compromise.     

Optimizing dose enhancement with Ta2O5 nanoparticles for synchrotron microbeam activated radiation therapy

Microbeam Radiation Therapy (MRT) exploits tumour selectivity and normal tissue sparing with spatially fractionated kilovoltage X-ray microbeams through the dose volume effect. Experimental measurements with Ta₂O₅ nanoparticles (NPs) in 9L gliosarcoma treated with MRT at the Australian Synchrotron, increased the treatment efficiency. Ta₂O₅ NPs were observed to form shells around cell nuclei which may be the reason for their efficiency in MRT. In this article, our experimental observation of NP shell formation is the basis of a Geant4 radiation transport study to characterise dose enhancement by Ta₂O₅ NPs in MRT. Our study showed that NP shells enhance the physical dose depending microbeam energy and their location relative to a single microbeam. For monochromatic microbeam energies below ∼70 keV, NP shells show highly localised dose enhancement due to the short range of associated secondary electrons. Low microbeam energies indicate better targeted treatment by allowing higher microbeam doses to be administered to tumours and better exploit the spatial fractionation related selectivity observed with MRT. For microbeam energies above ∼100 keV, NP shells extend the physical dose enhancement due to longer-range secondary electrons. Again, with NPs selectively internalised, the local effectiveness of MRT is expected to increase in the tumour. Dose enhancement produced by the shell aggregate varied more significantly in the cell population, depending on its location, when compared to a homogeneous NP distribution. These combined simulation and experimental data provide first evidence for optimising MRT through the incorporation of newly observed Ta₂O₅ NP distributions within 9L cancer cells.     

External beam radiation therapy with kilovoltage x-rays

Kilovoltage (kV) x-rays are most commonly used for diagnostic imaging due to their sensitivity to tissue composition. In radiation therapy (RT), due to their fast attenuation, kV x-rays are typically only used for superficial irradiation of skin cancer and for intra-operative RT (IORT). Recently, however, a number of kV RT techniques have emerged. In this review article, we provide a brief overview of the use of kV x-rays for RT.Various kV x-ray source technologies suitable for RT, such as conventional x-ray tubes as well as novel x-ray sources, are first described. This x-ray source section is then followed by a section on their implementation in terms of clinical, veterinary and preclinical applications. Specifically, IORT, superficial RT and dose enhancement with iodine and gold nanoparticles, as well as microbeam RT and FLASH RT are discussed in this context. Then, a number of kV x-ray RT applications in modeling and proof-of-principle stages, such as breast external beam RT with rotational sources, kilovoltage arc therapy and the BriXS Compton pulsed x-ray sources, are reviewed. Finally, some clinical and economic considerations for the development of kV RT techniques are discussed.     

Medical physics aspects of the synchrotron radiation therapies: Microbeam radiation therapy (MRT) and synchrotron stereotactic radiotherapy (SSRT)

Stereotactic Synchrotron Radiotherapy (SSRT) and Microbeam Radiation Therapy (MRT) are both novel approaches to treat brain tumor and potentially other tumors using synchrotron radiation. Although the techniques differ by their principles, SSRT and MRT share certain common aspects with the possibility of combining their advantages in the future. For MRT, the technique uses highly collimated, quasi-parallel arrays of X-ray microbeams between 50 and 600 keV. Important features of highly brilliant Synchrotron sources are a very small beam divergence and an extremely high dose rate. The minimal beam divergence allows the insertion of so called Multi Slit Collimators (MSC) to produce spatially fractionated beams of typically ∼25–75 micron-wide microplanar beams separated by wider (100–400 microns center-to-center(ctc)) spaces with a very sharp penumbra. Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents. The hypothesis of a selective radio-vulnerability of the tumor vasculature versus normal blood vessels by MRT was recently more solidified.SSRT (Synchrotron Stereotactic Radiotherapy) is based on a local drug uptake of high-Z elements in tumors followed by stereotactic irradiation with 80 keV photons to enhance the dose deposition only within the tumor. With SSRT already in its clinical trial stage at the ESRF, most medical physics problems are already solved and the implemented solutions are briefly described, while the medical physics aspects in MRT will be discussed in more detail in this paper.     

Retrospective comparison of rectal toxicity between carbon-ion radiotherapy and intensity-modulated radiation therapy based on treatment plan,normal tissue complication probability model,and clinical outcomes in prostate cancer

This retrospective study assessed the treatment planning data and clinical outcomes for 152 prostate cancer patients: 76 consecutive patients treated by carbon-ion radiation therapy and 76 consequtive patients treated by moderate hypo-fractionated intensity-modulated photon radiation therapy. These two modalities were compared using linear quadratic model equivalent doses in 2 Gy per fraction for rectal or rectal wall dose–volume histogram, 3.6 Gy per fraction-converted rectal dose–volume histogram, normal tissue complication probability model, and actual clinical outcomes. Carbon-ion radiation therapy was predicted to have a lower probability of rectal adverse events than intensity-modulated photon radiation therapy based on dose–volume histograms and normal tissue complication probability model. There was no difference in the clinical outcome of rectal adverse events between the two modalities compared in this study.     

Differentiation of normal and tumoral human keratinocytes cultured on dermis: Reconstruction of either normal or tumoral architecture

Summary Normal human keratinocytes isolated from skin and squamous carcinoma cells established from a human tumor (TR146 cell line) both exhibit limited morphologic differentiation when they are grown on conventional plastic dishes. However, when they are seeded on human de-epidermized dermis and cultured at the air-liquid interface, they are able to reform an epithelium having the morphology of the tissue of origin (i.e. skin or squamous carcinoma). The distribution in such reconstructed tissues of differentiation markers such as bullous pemphigoid antigen, 67K keratin, involucrin, membrane-bound transglutaminase, and filaggrin was very similar to their distribution in normal skin and squamous carcinoma specimens, respectively. The degree of differentiation is for both cell types extremely sensitive to culture conditions such as retinoic acid concentration, emersion of the cultures, etc. These results show that subcultured normal or tumoral keratinocytes are able to recover their specific morphogenetic potential when cultured in an environment close to their in vivo situation.     

Ultrasound-guided intraoperative electron beam radiation therapy: A phantom study

PurposeTo develop the method for ultrasound (US)-guided intra-operative electron beam radiation therapy (IOERT).MethodsWe first established the simulation, planning, and delivery methods for US-guided IOERT and constructed appropriate hardware (the multi-function applicator, accessories, and US phantom). We tested our US-guided IOERT method using this hardware and the Monte Carlo simulation IOERT treatment planning system (TPS). The IOERT TPS used a compensator to build the conformal dose distribution. Then, we used the TPS to evaluate the effect of setup uncertainty on target coverage by introducing phantom setup error ranging from 0 mm to 10 mm to the plans with and without the compensator.ResultsThe simulation, planning, and delivery methods for US-guided IOERT were introduced and validated on a phantom. A complete technique for US-guided IOERT was established. Target coverage decreased by about 12% and 29% as the phantom setup error increased to 5 mm and 10 mm for the plans with compensator, respectively. Without compensator, the corresponding target coverage decreases were 2% and 13%, respectively.ConclusionIn our study, we developed the multi-function applicator, US Phantom, and TPS for IOERT. The procedures included not only dose distribution planning, but also intraoperative US imaging, which provided the information necessary during surgery to improve IOERT quality assurance. Target coverage was more sensitive to setup errors with compensator compared to no compensator. Further studies are needed to validate the clinical efficacy of this US-guided IOERT method.     

Treatment outcomes and late toxicities of intensity-modulated radiation therapy for 1091 Japanese patients with localized prostate cancer

Aim

This study aimed to evaluate the treatment result of intensity-modulated radiation therapy (IMRT) in a large number of Japanese patients with prostate cancer.

Stereotactic ablative radiation therapy for spinal metastases: experience at a single Brazilian institution

BackgroundThis study aims to assess the clinical outcomes of patients with spine metastases who underwent stereotactic ablative radiation therapy (SABR) as part of their treatment. SABR has arisen as a contemporary treatment option for spinal metastasis patients with good prognoses.Materials and methodsBetween November 2010 and September 2018, Spinal SABR was performed in patients with metastatic disease in different settings: radical (SABR only), postoperative (after decompression and/or fixation surgery), and reirradiation. Local control (LC), pain control, overall survival (OS) and toxicities were reported.ResultsEighty-five patients (corresponding to 96 treatments) with spine metastases were included. The median age was 59 years (range, 23–91). In most SA BR (82.3%, n = 79) was performed as the first local spine treatment, while in 12 settings (12.5%), fixation and/or decompression surgery was performed prior to SABR. Two-year overall survival rate was 74.1%, and median survival was 19 months. The LC rate at 2 years was 72.3%. With regard to pain control, among 67 patients presenting with pain before SA BR, 83.3% had a complete response, 12.1% had a partial response, and 4.6% had progression. Vertebral compression fractures occurred in 10 patients (11.7%), of which 5 cases occurred in the reirradiation setting. Radiculopathy and myelopathy were not observed. No grade III or IV toxicities were seen.ConclusionThis is the first study presenting a Brazilian experience with spinal SA BR, and the results confirm its feasibility and safety. SABR was shown to produce good local and pain control rates with low rates of adverse events.     

Multi-strip silicon sensors for beam array monitoring in micro-beam radiation therapy

We present here the latest results from tests performed at the ESRF ID17 and ID21 beamlines for the characterization of novel beam monitors for Microbeam Radiation Therapy (MRT), which is currently being implemented at ID17. MRT aims at treating solid tumors by exploiting an array of evenly spaced microbeams, having an energy spectrum distributed between 27 and 600 keV and peaking at 100 keV. Given the high instantaneous dose delivered (up to 20 kGy/s), the position and the intensity of the microbeams has to be precisely and instantly monitored. For this purpose, we developed dedicated silicon microstrip beam monitors. We have successfully characterized them, both with a microbeam array at ID17, and a submicron scanning beam at ID21. We present here the latest results obtained in recent tests along with an outlook on future developments.     

Superparamagnetic iron oxide-enhanced MRI-guided stereotactic ablative radiation therapy for liver metastasis

BackgroundMRI-guided radiation therapy can image a target and irradiate it at the same time. Superparamagnetic iron oxide (SPIO) is a liver-specific contrast agent that can selectively visualize liver tumors, even if plain MRI does not depict them. The purpose of this study was to present a proof of concept of SPIO-enhanced MRI-guided radiation therapy for liver tumor.Case presentationMRI-guided stereotactic ablative radiation therapy (SABR) was planned for a patient with impaired renal function who developed liver metastases after nephroureterectomy for ureteral cancer. Because liver metastasis was not visualized on plain MRI, SPIO-enhanced MRI was performed at 0.35 T using true fast imaging with steady-state free precession (true FISP) pulse sequence and SABR was performed. Liver metastasis was clearly visualized by SPIO-enhanced MRI, and MRI-guided SABR was performed without adverse events.ConclusionEven if liver metastasis is not visualized by plain MRI, liver metastasis can be clearly depicted by administering SPIO, and MRI-guided radiation therapy can be performed.     

Intraoperative radiation therapy opportunities for clinical practice normalization: Data recording and innovative development

Background

Intraoperative radiotherapy (IORT) refers to the delivery of a high dose of radiation at the time of surgery.

Aim

To analyze clinical and research-oriented innovative activities developed in a 17-year period using intraoperative electron-radiation therapy (IOeRT) as a component of treatment in a multidisciplinary approach for cancer management.

Materials and methods

From 01/1995 to 03/2012 IOeRT procedures were registered in a specific Hospital-based database. Research and developments in imaging and recording for treatment planning implementation are active since 2006.

Results

1004 patients were treated and 1036 IORT procedures completed. Median age of patients was 61 (range 5 months to 94 years). Gender distribution was male in 54% of cases and female in 46%. Disease status at the time of IORT was 796 (77%) primary and 240 (23%) recurrent. Cancer type distribution included: 62% gastrointestinal, 18% sarcoma, 5% pancreas, 2% paediatric, 3% breast, 77 7% oligotopic recurrences, 2% other. IORT technical characteristics were: Applicator size 5 cm 22%, 6 cm 21%, 7 cm 21%, 8 cm 15%, 9 cm 6%, 10 cm 7% 12 cm 5% 15 cm 3%. Electron energies: 6 MeV 19%, 8 MeV 15%, 10 MeV 15%, 12 MeV 23%, 15 MeV 19%, 18 MeV 6%, other 3%. Multiple fields: 108 (11%). Dose: 7.5 Gy 3%, 10 Gy 35%, 12 Gy 3%, 12.5 Gy 49%, 15 Gy 5%, other 5%.

Conclusion

An IORT programme developed in an Academic Hospital based on practice-oriented medical decisions is an attractive interdisciplinary oncology initiative proven to be able to generate an intensive clinical activity for cancer patient quality care and a competitive source of scientific patient-oriented research, development and innovation.     

Lycopersicon esculentum lectin: an effective and versatile endothelial marker of normal and tumoral blood vessels in the central nervous system

The binding of Lycopersicon esculentum lectin (LEA) to the vascular endothelium was studied in the central nervous system of rat, mouse and guinea pig at different developmental ages, and in a gliosarcoma model. Our observations showed that LEA consistently stained the entire vascular tree in the spinal cord and in the brain of all animal species at all developmental ages investigated. In the tumor model, the staining of the vascular network was very reproducible, enabled an easy identification of vascular profiles and displayed a higher efficiency when compared to two other commonly used vascular marker (EHS laminin and PECAM-1). Moreover, our results showed that LEA staining was comparable in both vibratome and paraffin sections and could be easily combined with other markers in double labeling experiments. These observations indicate that LEA staining may represent an effective and versatile endothelial marker for the study of the vasculature of the central nervous system in different animal species and experimental conditions.     

Fifteen years of preclinical and clinical experiences about biotherapy treatment of lesions induced by accidental irradiation and radiotherapy

High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is therefore crucial. Because developments in cell therapy have brought some hope for the treatment of tissues damages induced by irradiation, the Institute for Radiation and Nuclear Safety contributed to establish the clinical guidelines for the management of accidentally irradiated victims and to provide the best supportive care to patients all over the world. In the past 15 years, we contributed to develop and test cell therapy for protection against radiation side effects in several animal models, and we proposed mechanisms to explain the benefit brought by this new therapeutic approach. We established the proof of concept that mesenchymal stem cells (MSCs) migrate to damaged tissues in the nonobese diabetic/severe combined immunodeficiency immunotolerant mice model and in non-human primate after radiation exposure. We showed that the intravenous injection of MSCs sustains hematopoiesis after total body irradiation, improves wound healing after radiodermatitis and protects gut function from irradiation damages. Thanks to a tight collaboration with clinicians from several French hospitals, we report successful treatments of therapeutic/accidental radiation damages in several victims with MSC infusions for hematopoiesis correction, radio-induced burns, gastrointestinal disorders and protection homeostatic functions of gut management after radio-therapy.     

Intelligence-guided beam angle optimization in treatment planning of intensity-modulated radiation therapy

An intelligence guided approach based on fuzzy inference system (FIS) was proposed to automate beam angle optimization in treatment planning of intensity-modulated radiation therapy (IMRT). The model of FIS is built on inference rules in describing the relationship between dose quality of IMRT plan and irradiated region of anatomical structure. Dose quality of IMRT plan is quantified by the difference between calculated and constraint doses of the anatomical structures in an IMRT plan. Irradiated region of anatomical structure is characterized by the metric, covered region of interest, which is the region of an anatomical structure under radiation field while beam’s eye-view is conform to target volume. Initially, an IMRT plan is created with a single beam. The dose difference is calculated for the input of FIS and the output of FIS is obtained with processing of fuzzy inference. Later, a set of candidate beams is generated for replacing the current beam. This process continues until no candidate beams is found. Then the next beam is added to the IMRT plan and optimized in the same way as the previous beam. The new beam keeps adding to the IMRT plan until the allowed beam number is reached. Two spinal cases were investigated in this study. The preliminary results show that dose quality of IMRT plans achieved by this approach is better than those achieved by the default approach with equally spaced beam setting. It is effective to find the optimal beam combination of IMRT plan with the intelligence-guided approach.     

Anatomy-based prediction method for determining ipsilateral lung doses in postoperative breast radiation therapy assisted by diagnostic computed tomography images

BackgroundThis study aimed to investigate whether ipsilateral lung doses (ILDs) could be predicted by anatomical indexes measured using diagnostic computed tomography (CT) prior to the planning stage of breast radiation therapy (RT).Materials and methodsThe thoracic diameters and the length of lines drawn manually were measured on diagnostic CT images. The parameters of interest were the skin maximum lung distance (sMLD), central lung distance (CLD), Haller index (HI), and body mass index (BMI). Lung dose-volume histograms were created with conformal planning, and the lung volumes receiving 5–40 Gy (V5–V40) were calculated. Linear regression models were used to investigate the correlations between the anatomical indexes and dose differences and to estimate the slope and 95% confidence intervals (CIs).ResultsA total of 160 patients who had undergone three-dimensional conformal RT after breast-conserving surgery were included. Univariable analysis revealed that the sMLD (p < 0.001), CLD (p < 0.001), HI (p = 0.002), and BMI (p < 0.001) were significantly correlated with the V20. However, multivariable analysis revealed that only the sMLD (slope: 0.147, p = 0.001, 95% CI: 0.162–0.306) and CLD (0.157, p = 0.005, 0.048–0.266) were strongly correlated with the V20. The p-value for the sMLD was the lowest among the p-values for all indexes, thereby indicating that the sMLD had the best predictive power for ILD.ConclusionssMLD and CLD are anatomical markers that can be used to predict ILD in whole breast RT. An sMLD > 20.5 mm or a CLD > 24.3 mm positively correlated with a high ILD.     

Addressing the dosimetric impact of bone cement and vertebroplasty in stereotactic body radiation therapy

PurposeBone cement used for vertebroplasty can affect the accuracy on the dose calculation of the radiation therapy treatment. In addition the CT values of high density objects themselves can be misrepresented in kVCT images. The aim of our study is then to propose a streamlined approach for estimating the real density of cement implants used in stereotactic body radiation therapy.MethodsSeveral samples of cement were manufactured and irradiated in order to investigate the impact of their composition on the radiation dose. The validity of the CT conversion method for a range of photon energies was investigated, for the studied samples and on six patients. Calculations and measurements were carried out with various overridden densities and dose prediction algorithms (AXB with dose-to-medium reporting or AAA) in order to find the effective density override.ResultsRelative dose differences of several percent were found between the dose measured and calculated downstream of the implant using an ion chamber and TPS or EPID dosimetry. If the correct density is assigned to the implant, calculations can provide clinically acceptable accuracy (gamma criteria of 3%/2 mm). The use of MV imaging significantly favors the attribution of a correct equivalent density to the implants compared to the use of kVCT images.ConclusionThe porosity and relative density of the various studied implants vary significantly. Bone cement density estimations can be characterized using MV imaging or planar in vivo dosimetry, which could help determining whether errors in dose calculations are due to incorrect densities.     

The role of radiation-induced apoptosis as a determinant of tumor responses to radiation therapy

Ionizing radiation is an effective means of killing tumor cells. Approximately 50% of all American cancer patients are treated with radiotherapy at some time during the course of their disease, making radiation one of the most widely used cytotoxic therapies. Currently, much effort is focused on understanding the molecular pathways that regulate tumor cell survival following radiotherapy, with the long term goal of developing novel therapeutic strategies for specifically sensitizing tumors to radiation. At present, there is particular interest in the role of tumor cell apoptotic potential as a regulator of both intrinsic and extrinsic determinants of the response of tumors to radiation therapy. Here we review what is currently known about the role of apoptosis as a mechanism of tumor cell killing by ionizing radiation and the relative contribution of apoptosis to cellular radiosensitivity and the ability to control human cancers using radiotherapy. The following topics will be discussed: (1) radiation-induced apoptosis in normal and malignant cells, (2) clinical findings with respect to apoptosis in human cancers treated with radiotherapy, (3) the contribution of apoptosis to intrinsic radiosensitivity in vitro, (4) the relevance of apoptosis to treatment outcome in experimental tumor models in vivo and (5) the potential of exploiting apoptosis as a means to improve the therapeutic efficacy of radiotherapy.