Potential of using cerium oxide nanoparticles for protecting healthy tissue during accelerated partial breast irradiation (APBI)

The purpose of this study is to investigate the feasibility of using cerium oxide nanoparticles (CONPs) as radical scavengers during accelerated partial breast irradiation (APBI) to protect normal tissue. We hypothesize that CONPs can be slowly released from the routinely used APBI balloon applicators—via a degradable coating—and protect the normal tissue on the border of the lumpectomy cavity over the duration of APBI. To assess the feasibility of this approach, we analytically calculated the initial concentration of CONPs required to protect normal breast tissue from reactive oxygen species (ROS) and the time required for the particles to diffuse to various distances from the lumpectomy wall. Given that cerium has a high atomic number, we took into account the possible inadvertent dose enhancement that could occur due to the photoelectric interactions with radiotherapy photons. To protect against a typical MammoSite treatment fraction of 3.4 Gy, 5 ng·g⁻¹ of CONPs is required to scavenge hydroxyl radicals and hydrogen peroxide. Using 2 nm sized NPs, with an initial concentration of 1 mg·g⁻¹, we found that 2–10 days of diffusion is required to obtain desired concentrations of CONPs in regions 1–2 cm away from the lumpectomy wall. The resultant dose enhancement factor (DEF) is less than 1.01 under such conditions. Our results predict that CONPs can be employed for radioprotection during APBI using a new design in which balloon applicators are coated with the NPs for sustained/controlled in-situ release from within the lumpectomy cavity.     

Measured microdosimetric spectra and therapeutic potential of boron neutron capture enhancement of 252Cf brachytherapy

Californium-252 is a neutron-emitting radioisotope used as a brachytherapy source for radioresistant tumors. Presented here are microdosimetric spectra measured as a function of simulated site diameter and distance from applicator tube 252Cf sources. These spectra were measured using miniature tissue-equivalent proportional counters (TEPCs). An investigation of the clinical potential of boron neutron capture (BNC) enhancement of 252Cf brachytherapy is also provided. The absorbed dose from the BNC reaction was measured using a boron-loaded miniature TEPC. Measured neutron, photon and BNC absorbed dose components are provided as a function of distance from the source. In general, the absorbed dose results show good agreement with results from other measurement techniques. A concomitant boost to 252Cf brachytherapy may be provided through the use of the BNC reaction. The potential magnitude of this BNC enhancement increases with increasing distance from the source and is capable of providing a therapeutic gain greater than 30% at a distance of 5 cm from the source, assuming currently achievable boron concentrations.     

Förster Resonance Energy Transfer Between Molecules in the Vicinity of Graphene-Coated Nanoparticles

The recent demonstration of the plasmonic-enhanced Förster resonance energy transfer (FRET) between two molecules in the vicinity of planar graphene monolayers is further investigated using graphene-coated nanoparticles (GNP). Due to the flexibility of these nanostructures in terms of their geometric (size) and dielectric (e.g., core material) properties, greater tunability of the FRET enhancement can be achieved employing the localized surface plasmons. It is found that while the typical characteristic graphene plasmonic enhancements are manifested from using these GNPs, even higher enhancements can be possible via doping and manipulating the core materials. In addition, the broadband characteristics are further expanded by the closely spaced multipolar plasmon resonances of the GNPs.     

Radiation-induced breast angiosarcoma: report of two patients after accelerated partial breast irradiation (APBI) and review of the literature

BackgroundAngiosarcoma may rarely complicate radiotherapy of breast cancer. This so-called radiation-induced angiosarcoma (RIAS) occurs in less than 0.3% of patients that underwent breast conservation surgeries, usually years after completion of radiotherapy.Case presentationwe introduce two cases of invasive ductal carcinoma who underwent lumpectomy and accelerated partial breast irradiation (APBI) as an alternative protocol to whole breast irradiation (WBI). They received adjuvant partial breast radiotherapy on tumor cavity for a total dose of 38.5 Gy in 10 fractions in 5 days using 3D-external-beam RT. In both cases, RIAS occurred eight years after radiotherapy, in the sub-cicatricial area in one patient and outside the irradiated area in the other one. They both underwent radical surgery and chemotherapy was performed in one patient.DiscussionThe underlying mechanism for development of RIAS is not well known, but its incidence seems to be increasing. RIAS after partial breast irradiation is very rare and has been reported in two cases so far. As it may be suggested in case 2, it is still a matter of debate if the risk of radiation-induced sarcoma is radiation-dose dependent. Although mastectomy is considered as a standard treatment, choice of treatment should be made according to the patient’s specifications.ConclusionThere are very few studies in the literature that report RIAS after APBI. Present study is the only one reporting two cases after the external 3D technique APBI. Prognosis of RIAS remains poor. Only a careful evaluation in a multidisciplinary context can offer to the patients the best result in terms of local control and survival.     

Effectiveness of different accelerated partial breast irradiation techniques for the treatment of breast cancer patients: Systematic review using indirect comparisons of randomized clinical trials

AimThis systematic review was conducted to compare the effectiveness of different accelerated partial breast irradiation (APBI) techniques for the treatment of breast cancer patients.BackgroundNumerous (APBI) techniques are available for clinical practice.Methods and materialsSystematic review of randomized controlled trials of APBI versus whole breast irradiation (WBI). The data from APBI studies were extracted for the analyses. Indirect comparisons were used to compare different APBI techniques.ResultsTen studies fulfilled the inclusion criteria. A total of 4343 patients were included, most of them with tumor stage T1-T2 and N0. Regarding APBI techniques, six trials used external beam radiation therapy; one intraoperative electrons; one intraoperative low-energy photons; one brachytherapy; and one external beam radiation therapy or brachytherapy. The indirect comparisons related to 5-years local control and 5-years overall survival were not significantly different between APBI techniques.ConclusionsBased on indirect comparisons, no differences in clinical outcomes were observed among diverse APBI techniques in published clinical trials that formally compared WBI to APBI. However wide confidence intervals and high risk of inconsistency precluded a sound conclusion. Further head-to-head clinical trials comparing different APBI techniques are required to confirm our findings. Studies comparing different techniques using individual participant data and/or real-life data from population-based studies/registries could also provide more robust results.     

Evaluation of size,morphology, concentration,and surface effect of gold nanoparticles on X-ray attenuation in computed tomography

Increasing attention has been focused on the use of nanostructures as contrast enhancement agents in medical imaging, especially in computed tomography (CT). To date, gold nanoparticles (GNPs) have been demonstrated to have great potential as contrast agents for CT imaging. This study was designed to evaluate any effect on X-ray attenuation that might result from employing GNPs with a variety of shapes, sizes, surface chemistries, and concentrations. Gold nanorods (GNRs) and spherical GNPs were synthesized for this application. X-ray attenuation was quantified by Hounsfield unit (HU) in CT. Our findings indicated that smaller spherical GNPs (13 nm) had higher X-ray attenuation than larger ones (60 nm) and GNRs with larger aspect ratio exhibited great effect on X-ray attenuation. Moreover, poly ethylene glycol (PEG) coating on GNRs declined X-ray attenuation as a result of limiting the aggregation of GNRs. We observed X-ray attenuation increased when mass concentration of GNPs was elevated. Overall, smaller spherical GNPs can be suggested as a better alternative to Omnipaque, a good contrast agent for CT imaging. This data can be also considered for the application of gold nanostructures in radiation dose enhancement where nanoparticles with high X-ray attenuation are applied.     

A review on gold nanoparticles radiosensitization effect in radiation therapy of cancer

In the recent years, application of nanoparticles in diagnosis and treatment of cancer has been the issue of extensive research. Among these studies some have focused on the dose enhancement effect of gold nanoparticles (GNPs) in radiation therapy of cancer. On the other hand, some studies indicated energy dependency of dose enhancement effect, and the others have studied the GNP size effect in association with photon energy. However, in some aspects of GNP-based radiotherapy the results of recent studies do not seem very conclusive in spite of relative agreement on the basic physical interaction of photoelectric between GNPs and low energy photons. The main idea behind the GNP dose enhancement in some studies is not able to explain the results especially in recent investigation on cell lines and animal models radiation therapy using GNPs. In the present article the results of the available reports and articles were analyzed and compared and the final status of the GNP-RT was discussed.     

Bone in the breast? Long term toxicity 21 years after interstitial brachytherapy as a boost

An 81-year-old patient developed an exulcerous tumor in her left breast 21 years after breast cancer treatment with lumpectomy and adjuvant radiotherapy. At the time of the initial treatment 21 years ago, whole breast irradiation was performed with a prescribed dose of 48?Gy and a maximal dose of 69?Gy. In addition, the patient received a 14.7?Gy boost with multicatheter brachytherapy as partial breast irradiation.In general, fat necrosis after radiotherapy, surgery or trauma is a minor problem for patients, but can lead to diagnostic difficulties. The incidence varies: the literature indicates that it occurs in up to 34% of cases. The direct pathogenesis is not clear; it can be due to high radiation dose to the breast, dosimetric inhomogeneities or surgical complications (seromas and inflammation).The tumor in the case described here, occurring more than two decades after the primary treatment, is a rarity in this extent and is an unusual clinical, radiological, and histological finding. It provides a good example of the need for an individualized approach to treatment.     

Intercomparison of dose enhancement ratio and secondary electron spectra for gold nanoparticles irradiated by X-rays calculated using multiple Monte Carlo simulation codes

PurposeTargeted radiation therapy has seen an increased interest in the past decade. In vitro and in vivo experiments showed enhanced radiation doses due to gold nanoparticles (GNPs) to tumors in mice and demonstrated a high potential for clinical application. However, finding a functionalized molecular formulation for actively targeting GNPs in tumor cells is challenging. Furthermore, the enhanced energy deposition by secondary electrons around GNPs, particularly by short-ranged Auger electrons is difficult to measure. Computational models, such as Monte Carlo (MC) radiation transport codes, have been used to estimate the physical quantities and effects of GNPs. However, as these codes differ from one to another, the reliability of physical and dosimetric quantities needs to be established at cellular and molecular levels, so that the subsequent biological effects can be assessed quantitatively.MethodsIn this work, irradiation of single GNPs of 50 nm and 100 nm diameter by X-ray spectra generated by 50 and 100 peak kilovoltages was simulated for a defined geometry setup, by applying multiple MC codes in the EURADOS framework.ResultsThe mean dose enhancement ratio of the first 10 nm-thick water shell around a 100 nm GNP ranges from 400 for 100 kVp X-rays to 600 for 50 kVp X-rays with large uncertainty factors up to 2.3.ConclusionsIt is concluded that the absolute dose enhancement effects have large uncertainties and need an inter-code intercomparison for a high quality assurance; relative properties may be a better measure until more experimental data is available to constrain the models.     

Metallic nanoparticle radiosensitisation of ion radiotherapy: A review

The use of gold nanoparticle (GNP) and other metal nanoparticle (MNP) radiosensitisers to enhance radiotherapy offers the potential of improved treatment outcomes. Originally intended for use with X-ray therapy, the possibility of enhanced hadron therapy is desirable due to the superior sparing of healthy tissue in hadron therapy compared to conventional X-ray therapy. While MNPs were not expected to be effective radiosensitisers for hadron therapy due to the limited Z dependence of interactions, recent experimental measurements have contradicted this expectation. Key experimental measurements and Monte Carlo simulations of MNP radiosensitisation for hadron irradiation are reviewed in the current work. Numerous experimental measurements have found a large radiosensitisation effect due to MNPs for proton and carbon ion irradiation. Experiments have also indicated that the radiosensitisation is due in large part to enhanced reactive oxygen species (ROS) production. Simulations have found a large radial dose and ROS enhancement on the nanoscale around a single MNP. However, the short range of the dose enhancement is insufficient for a large macroscale dose enhancement or enhanced biological effect in a cell model considering dose to the nucleus from GNPs in the cytoplasm (a distribution observed in most experiments).     

Dosimetric characteristics of the INTRABEAM ® system with spherical applicators in the presence of air gaps and tissue heterogeneities

The main aim of this study was to investigate the dosimetric characteristics of the INTRABEAM ® system in the presence of air gaps between the surface of applicators (APs) and tumor bed. Additionally, the effect of tissue heterogeneities was another focus. Investigating the dosimetric characteristics of the INTRABEAM® system is essential to deliver the required dose to the tumor bed correctly and reduce the delivered dose to the ribs and lung. Choosing the correct AP size and fitting it to the lumpectomy cavity is essential to remove the effect of air gaps and avoid inaccurate dose delivery. Consequently, the Geant4 toolkit was used to simulate the INTRABEAM ® system with spherical APs of various sizes. The wall effect of the ion chamber (IC) PTW 34013 used in the present study was checked. The simulations were validated in comparison with measurements, and then used to calculate any inaccuracies in dose delivery in the presence of 4- and 10-mm air gaps between the surface of the APs and the tumor bed. Also, the doses received due to tissue heterogeneities were characterized. It turned out that measurements and simulations were approximately in agreement (± 2%) for all sizes of APs. The perturbation factor introduced by the IC due to differences in graphite-coated polyethylene and air as compared to the phantom material was approximately equal to one for all AP. The greatest relative dose delivery difference was observed for an AP with a diameter of 1.5 cm, i.e., 44% and 70% in the presence of 4- and 10-mm air gaps, respectively. In contrast, the lowest relative dose delivery difference was observed for an AP with a diameter of 5 cm, i.e., 24% and 42% in the presence of 4- and 10-mm air gaps, respectively. Increasing APs size showed a decrease in relative dose delivery difference due to the presence of air gaps. In addition, the undesired dose received by the ribs turned out to be higher when a treatment site closer to the ribs was assumed. The undesired dose received by the ribs increased as the AP size increased. The lung dose turned out to be decreased due to the shielding effect of the ribs, small lung density, and long separation distance from the AP surface.     

Application of Monte Carlo calculations for validation of a treatment planning system in high dose rate brachytherapy

AimThe accuracy of treatment planning systems is of vital importance in treatment outcomes in brachytherapy. In the current study the accuracy of dose calculations of a high dose rate (HDR) brachytherapy treatment planning system (TPS) was validated using the Monte Carlo method.Materials and methodsThree ⁶⁰Co sources of the GZP6 afterloading brachytherapy system were modelled using MCNP4C Monte Carlo (MC) code. The dose distribution around all the sources was calculated by MC and a dedicated treatment planning system. The results of both methods were compared.ResultsThere was good agreement (<2%) between TPS and MC calculated dose distributions except at a point near the sources (<1 cm) and beyond the tip of the sources.ConclusionsOur study confirmed the accuracy of TPS calculated dose distributions for clinical use in HDR brachytherapy.     

Monte Carlo Study of Radiation Dose Enhancement by Gadolinium in Megavoltage and High Dose Rate Radiotherapy

MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed.     

On the need for massive additional shielding of a catheterization laboratory for the implementation of high dose rate 192Ir intravascular brachytherapy

Purpose: There is a widespread belief in the cardiology and radiation oncology community that high dose rate 192Ir intravascular brachytherapy cannot be implemented without massive additional shielding of the conventional catheterization labs. The purpose of this work is to show that this is a myth, which is not based on sound radiation protection principles.Methods: Exposure rates in air were calculated for a variety of point and line sources of 192Ir. Exposures per treatment at different distances from the source were calculated for a typical intravascular brachytherapy treatment of a 15-Gy dose at a radial distance of 2 mm from the source and for source lengths in the range of 0 to 10 cm. Additionally, exposure rates outside the catheterization lab were calculated for various lead shielding thicknesses typical of conventional X-ray facilities. These rates were used along with the NCRP recommendations on radiation facility design to assess shielding requirements.Results: For a treatment dose of 15 Gy at 2 mm, the occupational exposure per treatment at 2 m in air without any tissue attenuation or shielding was 7.8 mR for a lesion length of 3.0 cm. This exposure/treatment is independent of the dose rate or the activity of the source. However, it increases as lesion length is increased, increasing from 5.4 to 24.9 mR as lesion length increased from 2 to 10 cm. Exposures in unrestricted areas outside the catheterization lab using the NCRP shielding rationale can be kept below 2 mR per treatment and using appropriate workload, use, and occupancy factors below 2 mR per week.Conclusions: The feasibility of implementing a high dose rate 192Ir intravascular brachytherapy program in a catheterization laboratory is totally independent of the dose rate or the activity of the source. If it is feasible to implement 192Ir brachytherapy in a conventional catheterization lab using low activity 192Ir seeds, then it is also feasible to do so with a high activity 192Ir afterloader.     

Effect of step-down heating on brachytherapy in a murine tumor system

The effects of step-down heating combined with low-dose-rate irradiation (brachytherapy) were studied using a murine mammary adenocarcinoma (MTG-B) grown in the flanks of C3H mice. Treatment was initiated when tumors reached 0.9 to 1.1 cm in diameter. Step-down heating consisted of 7.5 min at 45 degrees C immediately followed by 7.5 min at 42 degrees C. Step-up heating consisted of 7.5 min at 42 degrees C immediately followed by 7.5 min at 45 degrees C. Step-down heating and step-up heating were compared to a single 45 degrees C, 15-min hyperthermia treatment. These hyperthermia protocols were combined before, in the middle of, or after brachytherapy. There were 4 untreated controls, 6 sham controls, and 11 treated animals in each of the brachytherapy-alone and combined treatment groups. The entire experiment was repeated at brachytherapy doses of 988, 1273, and 1603 cGy. In addition, the effects of step-down heating, step-up heating, and single-temperature hyperthermia were tested alone and in combination with sham treatment for each sequence. Based on daily measurements of tumor diameter, the growth delay to doubling volume was used as the biological end point. To compare the various treatment protocols, an isoeffect thermal enhancement ratio (TERiso) was calculated. Step-down heating after 988 cGy brachytherapy had a TERiso of 2.0 +/- 0.04, while step-up heating after 988 cGy brachytherapy had a TERiso of 1.7 +/- 0.05. Overall, the thermal enhancement ratios calculated from these growth delays indicate that step-down heating caused significantly greater hyperthermic radiosensitization than step-up heating when combined with brachytherapy.     

Thermal Chemosensitization of Breast Cancer Cells to Cyclophosphamide Treatment Using Folate Receptor Targeted Gold Nanoparticles

This article explores the application of hyperthermia mediated by alpha human folate receptor (αHFR) targeted gold nanoparticles (GNPs) for potentiating the cytotoxicity of cyclophosphamide (CPA) in αHFR positive breast cancer cells. Folate functionalized GNPs were delivered to highly αHFR positive breast cancer cells MDA-MB-231 and to MCF-7 breast cancer cells that does not express detectable levels of αHFR followed by hyperthermia. We have shown that hyperthermia induced by folate functionalized GNPs sensitized MDA-MB-231 cells by ten-fold to CPA treatment, whereas MCF-7 cells exhibited only onefold chemosensitization. Collectively, the study suggests the feasibility of using αHFR targeted GNPs for facilitating increased cellula r uptake of CPA in cancer cells expressing elevated αHFR, allowing reduction in drug dosage.     

Comparison of (125)I stereotactic brachytherapy and LINAC radiosurgery modalities based on physical dose distribution and radiobiological efficacy

The goal of this study was to make a comparison between stereotactic brachytherapy implants and linear accelerator-based radiosurgery of brain tumors with respect to physical dose distributions and radiobiological efficacy. Twenty-four treatment plans made for irradiation of brain tumors with low-dose-rate (125)I brachytherapy and multiple-arc LINAC-based radiosurgery were analyzed. Using the dose-volume histograms and the linear-quadratic model, the brachytherapy doses were compared to the brachytherapy-equivalent LINAC radiosurgery doses with respect to the predicted late effects of radiation on normal brain tissue. To characterize the conformity and homogeneity of dose distributions, the conformal index, external volume index, and relative homogeneity index were calculated for each dose plan and the mean values were compared. The average tumor volume was 5.6 cm(3) (range: 0.1-19.3 cm(3)). At low doses, the calculated radiobiological late effect on normal tissue was equivalent for external-beam and brachytherapy dose delivery. For brachytherapy at doses greater than 30 Gy, the calculated equivalent dose to normal tissues was less than for external-beam radiosurgery. However, the dose-calculated homogeneity was better for the LINAC radiosurgery, with a mean relative homogeneity index of 0.62 compared to the calculated value of 0.19 for the brachytherapy (P=0.0002). These results are only predictions based on calculations concerning normal tissue tolerance. More data and research are needed to understand the clinical relevance of these findings.     

The response of murine stem spermatogonia to radiation combined with 3-aminobenzamide

The influence of 3-aminobenzamide (3-AB) on the radiation response of the stem spermatogonia of the CBA mouse has been investigated. Doses of 3-AB from 66 to 450 mg/kg, administered 1 h before irradiation, significantly enhanced stem-cell killing. Enhancement was observed when 3-AB (450 mg/kg) was given up to 5 h before, but not if administered after, irradiation. When radiation was delivered at a lower dose rate (5 cGy/min compared to 180 cGy/min) significant dose sparing was achieved for radiation alone. Pretreatment with 3-AB resulted in slightly less enhancement at the low dose rate than at the high. Split-dose studies (9 Gy total dose) with radiation alone resulted in a recovery ratio of 1.4-1.5. Administration of 3-AB before the first dose resulted in a similar recovery ratio, but if given immediately after the first dose the ratio was smaller. Pretreatment of mice with the radiosensitizer RSU-1069 indicated that at least some of the stem cells were radiobiologically hypoxic. We suggest therefore that the enhancement of spermatogonial stem-cell killing by 3-AB is not entirely due to inhibition of repair processes but may also involve modification of the oxygen status of the testis.