Brian Keller

Design and characterization of HER-2-targeted gold nanoparticles for enhanced X-radiation treatment of locally advanced breast cancer.

Our purpose was to develop a human epidermal growth factor receptor-2 (HER-2) targeted nanotechnology-based radiosensitizer. HER-2 is overexpressed in 20-30% of all breast cancers and up to 2-fold higher in locally advanced disease (LABC). Trastuzumab was derivatized with a polyethylene glycol (OPSS-PEG-SVA) cross-linker to produce trastuzumab-PEG-OPSS. These immunoconjugates were analyzed by SDS-PAGE, and their immunoreactivity was assessed by flow cytometry using HER-2 overexpressing SK-BR-3 breast cancer cells. Reacting trastuzumab with increasing ratios of PEG resulted in an increase in molecular weight from approximately 148 kDa to 243 kDa, associated with increasing PEG substitution (0.6 to 18.9 PEG chains per trastuzumab). Attachment of approximately 7 PEG chains per trastuzumab resulted in 56% retention in immunoreactivity assessed by flow cytometry. The conjugates were then linked to 30 nm AuNPs. Using a novel (123)iodine-radiotracer based assay that overcomes the current limitations of spectrophotometric quantification of biological molecules on AuNPs we estimate 14.3 ± 2.7 antibodies were attached to each AuNP when 2 × 10(11) AuNPs were reacted with 20 μg of trastuzumab-PEG-OPSS. Specificity of trastuzumab-PEG-AuNPs for HER-2 and internalization in SK-BR-3 cells was demonstrated by comparing the uptake of trastuzumab-PEG-AuNPs or PEG-AuNPs by darkfield microscopy. The ability of trastuzumab-PEG-AuNPs in combination with 300 kVp X-rays to enhance DNA double strand breaks (DSBs) in SK-BR-3 cells was assessed by immunofluorescence using the γ-H2AX assay. γ-H2AX assay results revealed 5.1-fold higher DNA-DSBs with trastuzumab-PEG-AuNPs and X-radiation as compared to treatment with X-radiation alone. The trastuzumab-PEG-AuNPs are a promising targeted nanotechnology-based radiosensitizer for improving LABC therapy. The design and systematic approaches taken to surface modify and characterize trastuzumab-PEG-AuNPs described in this study would have application to other molecularly targeted AuNPs for cancer treatment.

Sensitivity of low energy brachytherapy Monte Carlo dose calculations to uncertainties in human tissue composition.

PURPOSE The objective of this work is to assess the sensitivity of Monte Carlo (MC) dose calculations to uncertainties in human tissue composition for a range of low photon energy brachytherapy sources:I125, P103d, C131s, and an electronic brachytherapy source (EBS). The low energy photons emitted by these sources make the dosimetry sensitive to variations in tissue atomic number due to the dominance of the photoelectric effect. This work reports dose to a small mass of water in medium Dw,m as opposed to dose to a small mass of medium in medium Dm,m. METHODS Mean adipose, mammary gland, and breast tissues (as uniform mixture of the aforementioned tissues) are investigated as well as compositions corresponding to one standard deviation from the mean. Prostate mean compositions from three different literature sources are also investigated. Three sets of MC simulations are performed with theGEANT4 code: (1) Dose calculations for idealized TG-43-like spherical geometries using point sources. Radial dose profiles obtained in different media are compared to assess the influence of compositional uncertainties. (2) Dose calculations for four clinical prostate LDR brachytherapy permanent seed implants using I125 seeds (Model 2301, Best Medical, Springfield, VA). The effect of varying the prostate composition in the planning target volume (PTV) is investigated by comparing PTV D90 values. (3) Dose calculations for four clinical breast LDR brachytherapy permanent seed implants using P103d seeds (Model 2335, Best Medical). The effects of varying the adipose/gland ratio in the PTV and of varying the elemental composition of adipose and gland within one standard deviation of the assumed mean composition are investigated by comparing PTV D90 values. For (2) and (3), the influence of using the mass density from CT scans instead of unit mass density is also assessed. RESULTS Results from simulation (1) show that variations in the mean compositions of tissues affect low energy brachytherapy dosimetry. Dose differences between mean and one standard deviation of the mean composition increasing with distance from the source are observed. It is established that theI125 and C131s sources are the least sensitive to variations in elemental compositions while P103d is most sensitive. The EBS falls in between and exhibits complex behavior due to significant spectral hardening. Results from simulation (2) show that two prostate compositions are dosimetrically equivalent to water while the third shows D90 differences of up to 4%. Results from simulation (3) show that breast is more sensitive than prostate with dose variations of up to 30% from water for 70% adipose/30% gland breast. The variability of the breast composition adds a ±10% dose variation. CONCLUSIONS Low energy brachytherapy dose distributions in tissue differ from water and are influenced by density, mean tissue composition, and patient-to-patient composition variations. The results support the use of a dose calculation algorithm accounting for heterogeneities such as MC. Since this work shows that variations in mean tissue compositions affect MC dosimetry and result in increased dose uncertainties, the authors conclude that imaging tools providing more accurate estimates of elemental compositions such as dual energy CT would be beneficial.

Tolerance and Acceptance Results of a Palladium-103 Permanent Breast Seed Implant Phase I/II Study

PURPOSE To test, in a prospective Phase I/II trial, a partial breast irradiation technique using a 103Pd permanent breast seed implant (PBSI) realized in a single 1-h procedure under sedation and local freezing. METHODS AND MATERIALS Eligible patients had infiltrating ductal carcinoma < or = 3 cm in diameter, surgical margin > or = 2 mm, no extensive intraductal component, no lymphovascular invasion, and negative lymph nodes. Patients received a permanent seed implant, and a minimal peripheral dose of 90 Gy was prescribed to the clinical target volume, with a margin of 1.5 cm. RESULTS From May 2004 to April 2007, 67 patients received the PBSI treatment. The procedure was well tolerated, with 17% of patients having significant pain after the procedure. Only 1 patient (1.5%) had an acute skin reaction (Grade 3 according to the National Cancer Institute Common Toxicity Criteria). The rates of acute moist desquamation, erythema, and indurations were 10.4%, 42%, and 27%, respectively. At 1 year the rate of Grade 1 telangiectasia was 14%. The rate of skin reaction decreased from 65% to 28% when skin received less than the 85% isodose. According to a Radiation Therapy Oncology Group questionnaire, 80-90% of patients were very satisfied with their treatment, and the remainder were satisfied. One patient (1.5%) developed an abscess, which resolved after the use of antibiotics. There was no recurrence after a median follow-up of 32 months (range, 11-49 months). CONCLUSIONS The feasibility, safety, and tolerability of PBSI compares favorably with that of external beam and other partial breast irradiation techniques.

Doses to internal organs for various breast radiation techniques--implications on the risk of secondary cancers and cardiomyopathy.

BackgroundBreast cancers are more frequently diagnosed at an early stage and currently have improved long term outcomes. Late normal tissue complications induced by adjuvant radiotherapy like secondary cancers or cardiomyopathy must now be avoided at all cost. Several new breast radiotherapy techniques have been developed and this work aims at comparing the scatter doses of internal organs for those techniques.MethodsA CT-scan of a typical early stage left breast cancer patient was used to describe a realistic anthropomorphic phantom in the MCNP Monte Carlo code. Dose tally detectors were placed in breasts, the heart, the ipsilateral lung, and the spleen. Five irradiation techniques were simulated: whole breast radiotherapy 50 Gy in 25 fractions using physical wedge or breast IMRT, 3D-CRT partial breast radiotherapy 38.5 Gy in 10 fractions, HDR brachytherapy delivering 34 Gy in 10 treatments, or Permanent Breast 103Pd Seed Implant delivering 90 Gy.ResultsFor external beam radiotherapy the wedge compensation technique yielded the largest doses to internal organs like the spleen or the heart, respectively 2,300 mSv and 2.7 Gy. Smaller scatter dose are induced using breast IMRT, respectively 810 mSv and 1.1 Gy, or 3D-CRT partial breast irradiation, respectively 130 mSv and 0.7 Gy. Dose to the lung is also smaller for IMRT and 3D-CRT compared to the wedge technique. For multicatheter HDR brachytherapy a large dose is delivered to the heart, 3.6 Gy, the spleen receives 1,171 mSv and the lung receives 2,471 mSv. These values are 44% higher in case of a balloon catheter. In contrast, breast seeds implant is associated with low dose to most internal organs.ConclusionsThe present data support the use of breast IMRT or virtual wedge technique instead of physical wedges for whole breast radiotherapy. Regarding partial breast irradiation techniques, low energy source brachytherapy and external beam 3D-CRT appear safer than 192Ir HDR techniques.

Monte Carlo study of LDR seed dosimetry with an application in a clinical brachytherapy breast implant

A Monte Carlo (MC) study was carried out to evaluate the effects of the interseed attenuation and the tissue composition for two models of 125I low dose rate (LDR) brachytherapy seeds (Medi-Physics 6711, IBt InterSource) in a permanent breast implant. The effect of the tissue composition was investigated because the breast localization presents heterogeneities such as glandular and adipose tissue surrounded by air, lungs, and ribs. The absolute MC dose calculations were benchmarked by comparison to the absolute dose obtained from experimental results. Before modeling a clinical case of an implant in heterogeneous breast, the effects of the tissue composition and the interseed attenuation were studied in homogeneous phantoms. To investigate the tissue composition effect, the dose along the transverse axis of the two seed models were calculated and compared in different materials. For each seed model, three seeds sharing the same transverse axis were simulated to evaluate the interseed effect in water as a function of the distance from the seed. A clinical study of a permanent breast 125I implant for a single patient was carried out using four dose calculation techniques: (1) A TG-43 based calculation, (2) a full MC simulation with realistic tissues and seed models, (3) a MC simulation in water and modeled seeds, and (4) a MC simulation without modeling the seed geometry but with realistic tissues. In the latter, a phase space file corresponding to the particles emitted from the external surface of the seed is used at each seed location. The results were compared by calculating the relevant clinical metrics V85, V100, and V200 for this kind of treatment in the target. D90 and D50 were also determined to evaluate the differences in dose and compare the results to the studies published for permanent prostate seed implants in literature. The experimental results are in agreement with the MC absolute doses (within 5% for EBT Gafchromic film and within 7% for TLD-100). Important differences between the dose along the transverse axis of the seed in water and in adipose tissue are obtained (10% at 3.5 cm). The comparisons between the full MC and the TG-43 calculations show that there are no significant differences for V85 and V100. For V200, 8.4% difference is found coming mainly from the tissue composition effect. Larger differences (about 10.5% for the model 6711 seed and about 13% for the InterSource125) are determined for D90 and D50. These differences depend on the composition of the breast tissue modeled in the simulation. A variation in percentage by mass of the mammary gland and adipose tissue can cause important differences in the clinical dose metrics V200, D90, and D50. Even if the authors can conclude that clinically, the differences in V85, V100, and V200 are acceptable in comparison to the large variation in dose in the treated volume, this work demonstrates that the development of a MC treatment planning system for LDR brachytherapy will improve the dose determination in the treated region and consequently the dose-outcome relationship, especially for the skin toxicity.

Evaluation of a commercial MRI Linac based Monte Carlo dose calculation algorithm with geant 4

PURPOSE This paper provides a comparison between a fast, commercial, in-patient Monte Carlo dose calculation algorithm (GPUMCD) and geant4. It also evaluates the dosimetric impact of the application of an external 1.5 T magnetic field. METHODS A stand-alone version of the Elekta™ GPUMCD algorithm, to be used within the Monaco treatment planning system to model dose for the Elekta™ magnetic resonance imaging (MRI) Linac, was compared against GEANT4 (v10.1). This was done in the presence or absence of a 1.5 T static magnetic field directed orthogonally to the radiation beam axis. Phantoms with material compositions of water, ICRU lung, ICRU compact-bone, and titanium were used for this purpose. Beams with 2 MeV monoenergetic photons as well as a 7 MV histogrammed spectrum representing the MRI Linac spectrum were emitted from a point source using a nominal source-to-surface distance of 142.5 cm. Field sizes ranged from 1.5 × 1.5 to 10 × 10 cm(2). Dose scoring was performed using a 3D grid comprising 1 mm(3) voxels. The production thresholds were equivalent for both codes. Results were analyzed based upon a voxel by voxel dose difference between the two codes and also using a volumetric gamma analysis. RESULTS Comparisons were drawn from central axis depth doses, cross beam profiles, and isodose contours. Both in the presence and absence of a 1.5 T static magnetic field the relative differences in doses scored along the beam central axis were less than 1% for the homogeneous water phantom and all results matched within a maximum of ±2% for heterogeneous phantoms. Volumetric gamma analysis indicated that more than 99% of the examined volume passed gamma criteria of 2%-2 mm (dose difference and distance to agreement, respectively). These criteria were chosen because the minimum primary statistical uncertainty in dose scoring voxels was 0.5%. The presence of the magnetic field affects the dose at the interface depending upon the density of the material on either sides of the interface. This effect varies with the field size. For example, at the water-lung interface a 33.94% increase in dose was observed (relative to the Dmax), by both GPUMCD and GEANT4 for the field size of 2 × 2 cm(2) (compared to no B-field case), which increased to 47.83% for the field size of 5 × 5 cm(2) in the presence of the magnetic field. Similarly, at the lung-water interface, the dose decreased by 19.21% (relative to Dmax) for a field size of 2 × 2 cm(2) and by 30.01% for 5 × 5 cm(2) field size. For more complex combinations of materials the dose deposition also becomes more complex. CONCLUSIONS The GPUMCD algorithm showed good agreement against GEANT4 both in the presence and absence of a 1.5 T external magnetic field. The application of 1.5 T magnetic field significantly alters the dose at the interfaces by either increasing or decreasing the dose depending upon the density of the material on either side of the interfaces.

Improvement of radiological penumbra using intermediate energy photons (IEP) for stereotactic radiosurgery

Using efficient immobilization and dedicated beam collimation devices, stereotactic radiosurgery ensures highly conformal treatment of small tumours with limited microscopic extension. One contribution to normal tissue irradiation remains the radiological penumbra. This work aims at demonstrating that intermediate energy photons (IEP), above orthovoltage but below megavoltage, improve dose distribution for stereotactic radiosurgery for small irradiation field sizes due to a dramatic reduction of radiological penumbra. Two different simulation systems were used: (i) Monte Carlo simulation to investigate the dose distribution of monoenergetic IEP between 100 keV and 1 MeV in water phantom; (ii) the Pinnacle3 TPS including a virtual IEP unit to investigate the dosimetry benefit of treating with 11 non-coplanar beams a 2 cm tumour in the middle of a brain adjacent to a 1 mm critical structure. Radiological penumbrae below 300 microm are generated for field size below 2 x 2 cm2 using monoenergetic IEP beams between 200 and 400 keV. An 800 kV beam generated in a 0.5 mm tungsten target maximizes the photon intensity in this range. Pinnacle3 confirms the dramatic reduction in penumbra size. DVHs show for a constant dose distribution conformality, improved dose distribution homogeneity and better sparing of critical structures using a 800 kV beam compared to a 6 MV beam.

Electron and photon spread contributions to the radiological penumbra for small monoenergetic x-ray beam (≤2 MeV)

Our team has previously published that submegavoltage photons could significantly improve the radiological penumbra for small size radiation fields. The present work uses Monte Carlo simulation to evaluate the contributions of secondary electrons and photon scatter to the penumbra region for various field sizes (5, 10, 20, and 40 mm in diameters) and for various monoenergetic photon beams (200, 400, 600, 800, 1000, and 2000 keV, and a standard 6 MV beam), minimizing geometrical and transmission penumbra. For field sizes less than 2 cm in diameter, photon scatter is negligible such that the secondary electrons are the main contributor to the radiological penumbra. Reducing the photon beam energy to the submegavoltage range reduces the range of secondary electrons and eventually improves the beam boundary sharpness. Provided that the geometrical penumbra and patient immobilization system are optimized, submegavoltage photon beams with effective photon energies in the 300 to 600 keV range, present significan...

Experimental measurement of radiological penumbra associated with intermediate energy x-rays (1 MV) and small radiosurgery field sizes

Stereotactic radiosurgery is used to treat intracranial lesions with a high degree of accuracy. At the present time, x-ray energies at or above Co-60 gamma rays are used. Previous Monte Carlo simulations have demonstrated that intermediate energy x-ray photons or IEPs (defined to be photons in the energy range of 0.2-1.2MeV), combined with small field sizes, produce a reduced radiological penumbra leading to a sharper dose gradient, improved dose homogeneity and sparing of critical anatomy adjacent to the target volume. This hypothesis is based on the fact that, for small x-ray fields, a dose outside the treatment volume is dictated mainly by the range of electrons set into motion by x-ray photons. The purpose of this work is: (1) to produce intermediate energy x rays using a detuned medical linear accelerator, (2) to characterize the energy of this beam, (3) to measure the radiological penumbra for IEPs and small fields to compare with that produced by 6MV x rays or Co-60, and (4) to compare these experimental measurements with Monte Carlo computer simulations. The maximum photon energy of our IEP x-ray spectrum was measured to be 1.2MeV. Gafchromic EBT films (ISP Technologies, Wayne, NJ) were irradiated and read using a novel digital microscopy imaging system with high spatial resolution. Under identical irradiation conditions the measured radiological penumbra widths (80%-20% distance), for field sizes ranging from 0.3×0.3to4.0×4.0cm2, varied from 0.3-0.77mm (1.2MV) and from 1.1-2.1mm (6MV). Even more dramatic were the differences found when comparing the 90%-10% or the 95%-5% widths, which are in fact more significant in radiotherapy. Monte Carlo simulations agreed well with the experimental findings. The reduction in radiological penumbra could be substantial for specific clinical situations such as in the treatment of an ocular melanoma abutting the macula or for the treatment of functional disorders such as trigeminal neuralgia (a nonlethal neurological pathology) where no long-term side effect should be induced by the treatment.

Permanent Breast Seed Implant Dosimetry Quality Assurance

PURPOSE A permanent breast seed implant is a novel method of accelerated partial breast irradiation for women with early-stage breast cancer. This article presents pre- and post-implant dosimetric data, relates these data to clinical outcomes, and makes recommendations for those interested in starting a program. METHODS AND MATERIALS A total of 95 consecutive patients were accrued into one of three clinical trials after breast-conserving surgery: a Phase I/II trial (67 patients with infiltrating ductal carcinoma); a Phase II registry trial (25 patients with infiltrating ductal carcinoma); or a multi-center Phase II trial for patients with ductal carcinoma in situ (3 patients). Contouring of the planning target volume (PTV) was done on a Pinnacle workstation and dosimetry calculations, including dose-volume histograms, were done using a Variseed planning computer. RESULTS The mean pre-implant PTV coverage for the V(90), V(100), V(150), and V(200) were as follows: 98.8% ± 1.2% (range, 94.5-100%); 97.3% ± 2.1% (range, 90.3-99.9%), 68.8% ± 14.3% (range, 32.7-91.5%); and 27.8% ± 8.6% (range, 15.1-62.3%). The effect of seed motion was characterized by post-implant dosimetry performed immediately after the implantation (same day) and at 2 months after the implantation. The mean V(100) changed from 85.6% to 88.4% (p = 0.004) and the mean V(200) changed from 36.2% to 48.3% (p < 0.001). Skin toxicity was associated with maximum skin dose (p = 0.014). CONCLUSIONS Preplanning dosimetry should aim for a V(90) of approximately 100%, a V(100) between 95% and 100%, and a V(200) between 20% and 30%, as these numbers are associated with no local recurrences to date and good patient tolerance. In general, the target volume coverage improved over the duration of the seed therapy. The maximum skin dose, defined as the average dose over the hottest 1 × 1-cm(2) surface area, should be limited to 90% of the prescription dose to minimize delayed skin toxicity.