Impact of spherical applicator diameter on relative biologic effectiveness of low energy IORT X-rays: A hybrid Monte Carlo study

IntroductionLow-kV IORT (Low kilovoltage intraoperative radiotherapy) using INTRABEAM machine and dedicated spherical applicators is a candidate modality for breast cancer treatment. The current study aims to quantify the RBE (relative biologic effectiveness) variations of emitted X-rays from the surface of different spherical applicators and bare probe through a hybrid Monte Carlo (MC) simulation approach.Materials and methodsA validated MC model of INTRABEAM machine and different applicator diameters, based on GEANT4 Toolkit, was employed for RBE evaluation. To doing so, scored X-ray energy spectra at the surface of each applicator diameter/bare probe were used to calculate the corresponding secondary electron energy spectra at various distances inside the water and breast tissue. Then, MCDS (Monte Carlo damage simulation) code was used to calculate the RBE values according to the calculated electron spectra.ResultsPresence of spherical applicators can increase the RBE of emitted X-rays from the bare probe by about 22.3%. In return, changing the applicator diameter has a minimal impact (about 3.2%) on RBE variation of emitted X-rays from each applicator surface. By increasing the distance from applicator surface, the RBE increments too, so that its value enhances by about 10% with moving from 2 to 10 mm distance. Calculated RBE values within the breast tissue were higher than those of water by about 4% maximum value.ConclusionBall section of spherical IORT applicators can affect the RBE value of the emitted X-rays from INTRABEAM machine. Increased RBE of breast tissue can reduce the prescribed dose for breast irradiation if INTRABEAM machine has been calibrated inside the water.     

Tumor therapy and track structure

The elevated relative biological effectiveness (RBE) of heavy ions like carbon is the main reason for their use in radiotherapy and is due to the microscopic distribution of dose inside each particle track. High local doses produce lesions that are expected to have a diminished possibility of repair. Thus, RBE depends on track structure and on the biological repair capacity of the tissue that is affected by the irradiation. For tumor treatment planning with heavy ions, the beam quality and the tissue sensitivity have to be taken into account. Using the dependence of radial dose distribution on particle energy and atomic number on the physical side and x-ray dose response for the repair capacity on the biological side, the response to particle irradiation can be calculated in the local effect model (LEM) and used for treatment planning. This article traces the route from electron emission as the basis of track structure to the RBE calculation and the application in treatment planning. Received: 21 April 1999 / Accepted in revised form: 1 September 1999     

Using electron beam radiation to simulate the dose distribution for whole body solar particle event proton exposure

As a part of the near solar system exploration program, astronauts may receive significant total body proton radiation exposures during a solar particle event (SPE). In the Center for Acute Radiation Research (CARR), symptoms of the acute radiation sickness syndrome induced by conventional radiation are being compared to those induced by SPE-like proton radiation, to determine the relative biological effectiveness (RBE) of SPE protons. In an SPE, the astronaut’s whole body will be exposed to radiation consisting mainly of protons with energies below 50 MeV. In addition to providing for a potentially higher RBE than conventional radiation, the energy distribution for an SPE will produce a relatively inhomogeneous total body dose distribution, with a significantly higher dose delivered to the skin and subcutaneous tissues than to the internal organs. These factors make it difficult to use a ⁶⁰Co standard for RBE comparisons in our experiments. Here, the novel concept of using megavoltage electron beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation is described. In these studies, Monte Carlo simulation was used to determine the dose distribution of electron beam radiation in small mammals such as mice and ferrets as well as large mammals such as pigs. These studies will help to better define the topography of the time-dose-fractionation versus biological response landscape for astronaut exposure to an SPE.     

Coupled field analysis of heat flow in the near field of a microwave applicator for tumor ablation

Microwave tumor ablation (MTA) offers a new approach for the treatment of hepatic neoplastic disease. Reliable and accurate information regarding the heat distribution inside biological tissue subjected to microwave thermal ablation is important for the efficient design of microwave applicators and for optimizing experiments, which aim to assess the effects of therapeutic treatments. Currently there are a variety of computational methods based on different vascular structures in tissue, which aim to model heat distribution during ablation. This paper presents results obtained from two such computational models for temperature distributions produced by a clinical 2.45 GHz MTA applicator immersed in unperfused ex vivo bovine liver, and compares them with measured results from a corresponding ex vivo experiment. The computational methods used to model the temperature distribution in tissue caused by the insertion of a 5.6 mm diameter "wandlike" microwave applicator are the Green's function method and the finite element method (FEM), both of which provide solutions of the heat diffusion partial differential equation. The results obtained from the coupled field simulations are shown to be in good agreement with a simplified analysis based on the bio-heat equation and with ex vivo measurements of the heat distribution produced by the clinical MTA applicator.     

The suitability of negative pions for radiotherapy: 4 years preclinical research with the biomedicalΠE3-beam at SIN

Summary The radiobiological experiences over 4 years research with the biomedical pion channel of the 590 MeV proton-accelerator of the Swiss Institute for Nuclear Research (SIN) have been summarized. Mainly sensitive biological systems have been chosen (limiting factor: dose-rate not more than 10 rad/min, exceptionally till 30 rad/min). The RBE values in the peak region vary between 0.7–3.3 and in the plateau region between 0.4–1. The gain factors for pion radiotherapy of cancer are, beside the excellent physical dose distribution, irradiation in the same treatment with two types of radiation: sparsely ionizing (low LET) radiation in plateau (healthy tissue) region and densely ionizing (high LET) radiation in peak (tumor) region. The biological effectiveness ratio in peak and plateau as the clinically most important relation vary between 1.4–4.2. This is valid also for clinically limiting factors such as reaction of skin, of small intestine, vascular damage, dominant lethals in hypoxic cells, tumor induction. For peak pions the RBE in hypoxic cells (tumor cells) can be much higher than in euoxic cells (healthy tissue). This preclinical work supports the hope in a highly effective cancer therapy with negative pions.Supported by the Swiss National Science Foundation (grant no. 3.682-0.75) and the Swiss Mobilar Insurance Company     

Vascular and epithelial damage in the lung of the mouse after X rays or neutrons

The response of the lung was studied in CFLP mice after exposure of the whole thorax to X rays (250 kVp) or cyclotron neutrons (16 MeV deuterons on Be, mean energy 7.5 MeV). To measure blood volume and leakage of plasma proteins, 51Cr-labeled red blood cells and 125I-albumin were injected intravenously and 24 h later lungs were lavaged via the trachea. Radioactivities in lung tissue and lavage fluid were determined to estimate the accumulation of albumin in the interstitial and alveolar spaces indicating damage to blood vessels and alveolar epithelium respectively. Function of type II pneumonocytes was assessed by the amounts of surfactant (assayed as lipid phosphorous) released into the lavage fluid. During the first 6 weeks, lavage protein and surfactant were increased, the neutron relative biological effectiveness (RBE) being unity. During pneumonitis at 12-24 weeks, surfactant levels were normal, blood volume was decreased, and both interstitial and alveolar albumin were increased. Albumin levels then decreased. At late times after exposure (42-64 weeks) alveolar albumin returned to normal but interstitial albumin was still slightly elevated. Values of RBE for changes in blood volume and interstitial and alveolar albumin at 15 weeks and for changes in blood volume and interstitial albumin at 46 weeks were 1.4, comparable with that for animal survival at 180 days. The results indicate that surfactant production is not critical for animal survival. They suggest that changes in blood vessels and alveolar epithelium occur during acute pneumonitis; epithelial repair follows but some vascular damage may persist. The time course of the changes in albumin levels did not correlate with increases in collagen biosynthesis which have been observed as early as 1 month after exposure and persist for up to 1 year. Furthermore, a dose which had no effect on leakage caused a marked increase in collagen biosynthesis. Thus the present results do not support a causal relationship between exudation of vascular protein during pneumonitis and the later development of fibrosis.     

Dose-response curves for late functional changes in the normal rat brain after single carbon-on doses evaluated by magnetic resonance imaging: influence of follow-up time and calculation of relative biological effectiveness

This study investigated late effects in the brain after irradiation with carbon ions using a rat model. Thirty-six animals were irradiated stereotactically at the right frontal lobe using an extended Bragg peak with maximum doses between 15.2 and 29.2 Gy. Dose-response curves for late changes in the normal brain were measured using T1- and T2-weighted magnetic resonance imaging (MRI). Tolerance doses were calculated at several effect probability levels and times after irradiation. The MRI changes were progressive in time up to 17 months and remained stationary after that time. At 20 months the tolerance doses at the 50% effect probability level were 20.3 +/- 2.0 Gy and 22.6 +/- 2.0 Gy for changes in T1- and T2-weighted MRI, respectively. The relative biological effectiveness (RBE) was calculated on the basis of a previous animal study with photons. Using tolerance doses at the 50% effect probability level, RBE values of 1.95 +/- 0.20 and 1.88 +/- 0.18 were obtained for T1- and T2-weighted MRI. A comparison with data in the literature for the spinal cord yielded good agreement, indicating that the RBE values for single-dose irradiations of the brain and the spinal cord are the same within the experimental uncertainty.     

RBEs of thermal neutron capture therapy and 10B(n, alpha)7 Li reaction on melanoma-bearing hamsters

Using Greene's melanoma transplanted into Syrian (golden) hamsters, we determined the relative biological effectiveness (RBE) of thermal neutron capture therapy (TNCT) using 10B-paraboronophenylalanine (10B-BPA) in comparison with a 9-MeV electron beam. We also obtained the RBE of the 10B(n, alpha)7 Li reaction by calculation based on summed dose data from TNCT. Throughout this study, the Kyoto University Research Reactor was used as the source for thermal neutrons; the reactor was specially altered to attain a low contamination level both for gamma-rays and fast neutrons. 10B-BPA was administered 8 hours before thermal neutron irradiation to the hamsters with melanoma. The tumor was then irradiated at 5 MW for 90 minutes. The absorbed dose from this TNCT was calculated by the method of Fairchild and Goodman (Phys. Med. Biol. 1966; 2:15-30). The RBEs of the TNCT and the 10B(n, alpha)7 Li reaction obtained by the tumor growth delay time (TGDT) method were 2.22 and 2.51, respectively, at 10.5 days of TGDT. These RBE values varied with TGDT and the absorbed dose. The RBE value of TNCT had a peak at 7.0 days of TGDT; that of the 10B(n, alpha)7Li reaction was higher at a low absorbed dose level and lower at a high absorbed dose level.     

RBE/absorbed dose relationship of d(50)-Be neutrons determine for early intestinal tolerance in mice]

RBE/absorbed dose realtionship of d(50)-Be neutrons (ref.: 60Co) was determined using intestinal tolerance in mice (LD50) after single and fractionated irradiation. RBE is 1.8 for a single fraction (about 1000 rad 60Co dose); it increases when decreasing dose and reaches the plateau value of 2.8 for a 60Co dose of about 200 rad. This RBE value is used for the clinical applications with the cyclotron "Cyclone" at Louvain-la-Neuve.     

Light- and electron-microscopic study of the rat esophagus following intraluminal argon laser irradiation

36 rat esophagi were irradiated by argon laser via an applicator with circumferential light distribution. They were perfused with glutaraldehyde and studied by light and transmission electron microscopy immediately, 2 days and 14 days after irradiation. Immediately after irradiation the laser center showed destruction of the keratinized stratified squamous epithelium. The collagenous fibers of the connective tissue were altered; fibrocytes and fibroblasts were severely damaged, and the microvascular lumina were occluded. The smooth muscle tissue and skeletal muscle tissue showed myofilament defects and initial karyonecrosis. There was decreasing damage of both fiber types up to 4 mm from the laser center. After 2 days the morphology of the laser center was not different from that seen immediately after irradiation. At a distance of 2 mm a partly differentiated new epithelium emerged below the necrotic epithelium. An inflammatory reaction was found in the connective tissue. After 14 days the esophageal wall was replaced and the lumen was occluded by young granulation tissue in the former laser center. Peripherally the esophageal wall appeared almost normal. As the rat esophagus serves as a model for esophagotracheal fistulae in newborn children, our findings indicate that the argon laser should be capable of occluding these fistulae likewise.     

Assessment of clinically relevant dose distributions in pelvic IOERT using Gafchromic EBT3 films

PurposeIn IOERT a single dose of radiation is delivered to the tumour site during surgery. Manual dose calculations are used and the irradiation target volume, electron energy and applicator are decided on site by the radiation oncologist. This work assesses the effect that irregular and curved surfaces, typical of pelvic IOERT, may have on the expected dose distribution.MethodsThe feasibility of using Gafchromic EBT3 films and a slab phantom to obtain 2D dose distributions was investigated. Different set-ups were tested by comparison with water tank measurements, applying the gamma function analysis with 2% and 2 mm criteria. The validated set-up was then used to obtain reference dose distributions, which were converted to colour-coded graphical representations. Phantoms with step-like and curved surfaces were created to simulate typical pelvic IOERT irradiation surfaces, and the dose distributions were obtained and compared with the reference distributions.ResultsGood agreement with water tank measurements was obtained for all applicators below 2 mm, using the chosen setup in reference conditions. In non-reference conditions, the presence of a step-like surface creates an adjacent hotspot, followed by a quick reduction of the dose in depth. With curved surfaces, the dose distribution is shifted forward, becoming curved and deeper, but when the applicator is larger than the hole, hotspots are also observed.ConclusionsThe shape of the irradiation surfaces alters the dose distribution. Visualization of these effects is important to assess target coverage and interpret in vivo measurements in pelvic IOERT.     

Relative biological effectiveness (RBE) of low-dose californium-252

Relative biological effectiveness (RBE) of 252Cf, with respect to 192Ir, has been determined at the low dose rates commonly used in interstitial and intracavitary therapy. The biological criterion was growth reduction in Vicia faba bean roots. Two varieties of Vicia faba were used. For Vicia faba Sutton's seeds, an RBE of 5.7 to 6.6 was obtained for 252Cf Dn + gamma doses of 0.5 to 0.2 Gy respectively and at a Dn + gamma dose rate of 0.11 Gy-1. The gamma contribution D gamma/Dn + gamma at the level of the root tipes was 0.35 and the derived RBE of the neutron emission of 252Cf was then 8.2 to 9.7. For Vicia faba Be1B and in the same irradiation conditions, an RBE of 5.1 to 6.2 was obtained for the total (n + gamma) 252Cf emission and for Dn + gamma doses of 0.4 to 0.2 Gy respectively. These values lead to an RBE of 7.4 to 9.0 for the neutron emission of 252Cf. For Vicia faba BelB, but for another source arrangement (Dn + gamma dose rate of 0.13 Gy . h-1 for 252Cf), an RBE of 5.6 to 7.5 was obtained for the total (n + gamma) emission of 252Cf and for Dn + gamma doses of 0.4 to 0.1 Gy respectively. The gamma contribution (D gamma/Dn + gamma) at the level of the root tips was 0.42, and the derived RBE of the neutron emission of 252Cf was then 8.9-12.3.     

Dosimetric characterization of INTRABEAM® miniature accelerator flat and surface applicators for dermatologic applications

PurposeThis study aims at characterizing the dosimetric behavior of an INTRABEAM^® miniature accelerator equipped with flat and surface applicators, converting the spherical dose distribution into a flat one.MethodsDosimetric characterization was carried out in two steps. Firstly characterization was made in standard conditions for dermatologic applications, which is with the applicator directly on contact with the skin. Secondly, characterization was made in more clinical conditions, such as obliquities and heterogeneities.ResultsBehaviors of flat and surface applicators are different. Dose distribution for surface applicators is uniform at surface, whereas for flat applicator the maximum homogeneity is shown at a particular depth in water. Some results are different from previously published studies due to differences in the X-ray source design. The study showed that in the absence of a perfect contact between the applicator and the skin of the patient, there is a dose distribution spread on the edge of the irradiation field where the contact is not made. Dose loss due to lack of backscatter radiations is significant. By contrast, influence of a denser material behind the measurement point has no significant influence on the dose at this point. Thickness of tissue treated with flat and surface applicators is only a few millimeters, depending on the applicator's size, making these applicators ideal for superficial lesions, compared to high energy electrons and iridium brachytherapy.ConclusionsThe INTRABEAM^® miniature accelerator equipped with surface applicators is a reliable way of treating superficial cutaneous malignancies.     

Axitinib Improves Radiotherapy in Murine Xenograft Lung Tumors

A third of patients with non-small cell lung cancer (NSCLC) present with un-resectable stage III locally advanced disease and are currently treated by chemo-radiotherapy but the median survival is only about 21 months. Using an orthotopic xenograft model of lung carcinoma, we have investigated the combination of radiotherapy with the anti-angiogenic drug axitinib (AG-013736, Pfizer), which is a small molecule receptor tyrosine kinase inhibitor that selectively targets the signal transduction induced by VEGF binding to VEGFR receptors. We have tested the combination of axitinib with radiotherapy in nude mice bearing human NSCLC A549 lung tumors. The therapy effect was quantitatively evaluated in lung tumor nodules. The modulation of radiation-induced pneumonitis, vascular damage and fibrosis by axitinib was assessed in lung tissue. Lung irradiation combined with long-term axitinib treatment was safe resulting in minimal weight loss and no vascular injury in heart, liver and kidney tissues. A significant decrease in the size of lung tumor nodules was observed with either axitinib or radiation, associated with a decrease in Ki-67 staining and a heavy infiltration of inflammatory cells in tumor nodules. The lungs of mice treated with radiation and axitinib showed a complete response with no detectable residual tumor nodules. A decrease in pneumonitis, vascular damage and fibrosis were observed in lung tissues from mice treated with radiation and axitinib. Our studies suggest that axitinib is a potent and safe drug to use in conjunction with radiotherapy for lung cancer that could also act as a radioprotector for lung tissue by reducing pneumonitis and fibrosis.     

Relative biological effectiveness of high-energy photons (up to 50 MV) and electrons (50 MeV)

In vitro studies of the relative biological effectiveness (RBE) of 50-MV X rays have shown an RBE of 1.1 relative to 4-MV X rays. This will be important in clinical radiotherapy. The aim of this study was to verify these results and to investigate whether photonuclear processes might cause the difference in RBE. To do so, 50- and 20-MV X rays and 50-MeV electrons were investigated with respect to RBE. Chinese hamster V79 cells were irradiated in a specially designed system which allows for a high reproducibility of geometry and dosimetry. Fractionation experiments were also carried out to establish the RBE at the clinically relevant dose level, 2 Gy. Fricke dosimetry was used, and the results were confirmed with ionization chamber measurements. The RBE for 50-MV X rays was estimated to be 1.14 at a surviving fraction of 0.1 and 1.12 at a surviving fraction of 0.01. The RBEs for the other qualities were equal to one. The RBE calculated for the 2 Gy/fraction experiments was 1.17.     

The RBE for skin tumors and hair follicle damage in the rat following irradiation with alpha particles and electrons

Rat skin was irradiated with cyclotron-accelerated alpha particles with doses ranging from 210 rads to 6850 rads and monoenergetic electrons with doses ranging from 810 rads to 12,300 rads. The beams were modified so that the depth-dose curves were approximately identical with penetrations of about 1.0 mm. Tumors were counted every 4 weeks for 80 weeks, and at death or sacrifice the hair follicle damage was assessed by using "whole mounts" of separated epithelium. The RBE values determined from a comparison of the dose response curves were: acute skin injury, RBE = 3.0+/-1.0; hair follicle survival, RBE = 2.1 +/- 0.7; hair follicle damage, RBE = 2.6 = 0.4; tumor induction, RBE = 2.9+/- 0.5. Within the experimental error, these values were independent of the dose. For both types of radiation, the tumor incidence increased approximately as the square of time and at low doses approximately as the 4th power of dose. The histological characteristics of the tumors and the correlation between the incidence of tumors and damaged hair follicles were independent of the type of radiation. The results were consistent with the hypothesis that structural damage to the hair follicles is a factor in the tumor induction process.     

Dose-response curves and tolerance doses for late functional changes in the normal rat brain after stereotactic radiosurgery evaluated by magnetic resonance imaging: influence of end points and follow-up time

Late reaction of normal tissue is still a limiting factor in radiotherapy and radiosurgery of patients with brain tumors. Few quantitative data in terms of dose-response curves are available. In the present study, 99 animals were irradiated stereotactically at the right frontal lobe using a linear accelerator and single doses between 26 and 50 Gy. The diameter of the spherical dose distribution was 4.7 mm (80% isodose). Dose-response curves for late changes in the normal brain at 20 months were measured using T1- and T2-weighted magnetic resonance imaging (MRI). The dependence of the dose-response curves on the follow-up time and the definition of the biological end point were determined. Tolerance doses were calculated at several effect probability levels and times after irradiation. The MRI changes were found to be dependent on dose and progressive in time. At 20 months, the tolerance doses at a 50% effect probability level were 39.6 +/- 1.0 Gy and 42.4 +/- 1.4 Gy for changes in T1- and T2-weighted images, respectively. These dose-response curves can be used for further quantitative investigations on the influence of various treatment parameters, such as the application of charged particles, radiopharmaceuticals or the variation of tissue oxygenation.     

Influence of different Fletcher–Suit applicator geometries on sagittal dose distribution

IntroductionOne of the brachytherapy treatment modality of cervix carcinomas is insertion with Fletcher–Suit (FS) applicator. Depending on the patient anatomy and pathology and on the construction of the FS applicator different geometrical arrangements in ovoid separation, in ovoids' sagittal level with respect to the tandem were experienced. The multiple insertions show minor differences in applicator geometries. The aim of the study is to evaluate the influence of main geometrical parameters: the ovoid separation, symmetry and the ovoids' sagittal shift on dose distribution in different FS applicator arrangements. We tested the effect of dwell time settings in improvement of dose distribution of less adequate insertions. We also investigated the effect of inter-fractional variation of applicator geometry.Materials and methodsWe considered 73 treatment fractions of 22 patients. All insertions were performed by the same gynaecologist with the same type of FS applicator, while the treatment plans were generated by the same physicist using the same treatment planning method. We compared the sagittal dose distribution of different FS applicator geometries with dose levels at two applicator points, defined 2 cm apart from the tandem towards the bladder and rectum. We computed the Pearson correlation coefficients between the dose levels at the applicator points and the ovoid separation, symmetry and the ovoids' sagittal shift. We also investigated the effect of dwell time settings in ovoids in order to decrease the dose to organs at risk. The inter-fractional variation of the FS applicator geometries and the influence on the dose levels at the two applicator points were also tested.Results and conclusionsStrong correlation was found between the ovoid separation and dose values to applicator points defined in sagittal direction of FS applicator arrangements. Also strong correlation was between the ovoids' sagittal position with respect to the tandem and the applicator point defined towards the rectum, while the ovoid symmetry had no influence on the sagittal dose distribution. The standard deviations of inter-fractional variation of the ovoid separation and the ovoids' sagittal position were within ±5.2 mm and ±10.2 mm respectively. The inter-fractional variations in FS applicator geometry resulted in variation in dose levels at the applicator points ±0.8 Gy typically, while the largest value was ±1.6 Gy.     

Analysis of chromosome aberrations in human peripheral lymphocytes induced by in vitro α-particle irradiation

Irradiation of human lymphocytes by α-particles under different conditions has been seen to be substantially more effective in the induction of dicentric chromosomes than irradiation by ψ-rays. However, the relative biological effectiveness (RBE) determined in these studies RBE are likely to be due in part to differing exposure conditions. Therefore, a technique designed to insure iniformity of irradiation was developed in the present study, and complications due to the cell cycle kinetics were controlled. After stimulation with phytohaemagglutinin (PHA), separated lymphocytes were allowed to attach for 3 h to the thin foil bottom of an irradiation chamber. Cell monolayers were exposed with α-particles from²⁴¹Am. Strong over-dispersion was noted for the cell-to-cell variance of the number of dicentrics. The dose response of dicentrics was linear, with a yield of 0.27 dicentrics per cell and per Gy. This corresponds to a low dose RBE of 15 relative to¹³⁷Cs γ-ray exposure under the same experimental conditions.