Clinical applications of high dose rate endorectal brachytherapy for patients with rectal cancer.

With the establishment of total mesorectal excision for the treatment of rectal cancer, local recurrence rates have significantly decreased. The addition of preoperative external beam irradiation further reduces this risk to less than 6%. As the local treatment becomes successful and more widely used, the associated treatment-related toxicity is becoming clinically important. If 4 to 6% of the patients are to benefit from neo-adjuvant therapy before total mesorectal excision, the acute and the long-term toxicity burden must be reasonable. With the introduction of better-quality imaging for tumour visualization and treatment planning, a new-targeted radiation treatment was introduced with high dose rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies first in the preoperative setting, then as a boost after external beam radiation therapy as a dose escalation study to achieve higher tumour local control in a radical treatment setting with no surgery. High dose rate endorectal brachytherapy is safe and effective in achieving high tumour regression rate and was well tolerated. It is presently explored in a phase III dose escalation study in the non-operative management of patients with operable rectal cancer.

Validation of a new fluidic device for mechanical stimulation and characterization of microspheres: A first step towards cartilage characterization.

Articular cartilage is made of chondrocytes surrounded by their extracellular matrix that can both sense and respond to various mechanical stimuli. One of the most widely used in vitro model to study cartilage growth is the model of mesenchymal stromal cells-derived cartilage micropellet. However, mechanical stimulation of micropellets has never been reported probably because of their small size and imperfect round shape. The objective of the study was to develop an original custom-made device allowing both the mechanical stimulation and characterization of cartilage micropellets. The fluidic-based device was designed for the concomitant stimulation or characterization of six microspheres placed into the conical wells of a tank. In the present study, the device was validated using alginate-, collagen- and crosslinked collagen-based microspheres. Different types and ranges of pressure signals (square, sinusoidal and constant) were applied. The mechanical properties of microspheres were equivalent to those determined by a conventional compression test. Accuracy, repeatability and reproducibility of all types of pressure signals were demonstrated even though square signals were less accurate and sinusoidal signals were less reproducible than the others. The interest of this new device lies in the reliability to mechanically stimulate and characterize microspheres with diameters in the range of 900 to 1500 µm. Mechanical stimulation can be performed on six microspheres in parallel allowing the mechanical and molecular characterization of the same group of cartilage micropellets. The device will be useful to evaluate the growth of cartilage micropellets under mechanical stimuli.

Calibration of MTT assay in proton beams using radiochromic films.

PURPOSE: This study provides methodology of calibrating as well as controlling the output for an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay irradiated in a low energy proton beam using EBT3-model GAFCHROMICTM film, without correcting for quenching effect. METHODS: A calibrated Markus ionization chamber was used to measure the depth dose and beam output for 26.5 MeV protons produced by a CS30 cyclotron. A time-controlled aluminum cylinder was added in front of the horizontal beam-exit serving as a radiation shutter. Following the TRS-398 reference dosimetry protocol for proton beams, the output was calibrated in water at a reference depth of 3 mm. EBT3 film was calibrated for doses up to 8 Gy at the same depth. To verify the dose distribution for each 96-well MTT assay plate, EBT3 film was placed at the reference depth during irradiation and cell doses were scaled by measured percent depth dose (PDD) data. RESULTS: The radiochromic film dosimetry system in this study provides dose measurements with an uncertainty better than 3.3% for doses higher than 1 Gy. From a single exposure and utilizing the Gaussian shape of the beam, multiple dose points can be obtained within different wells of the same plate ranging from 6.9 Gy (sigma ∼4%) in the central well, and 2 Gy (sigma ∼8%) for wells positioned closer to the periphery. CONCLUSIONS: We described a methodology for radiochromic film-based dose monitoring system, using low-energy protons, which can be used for the MTT assay in any proton beam, except within Bragg peak region.

CT-based adaptive high-dose-rate endorectal brachytherapy in the preoperative treatment of locally advanced rectal cancer: Technical and practical aspects.

PURPOSE: During the last decade due to the availability of a CT scan in the brachytherapy suite, high-dose-rate endorectal brachytherapy (HDREBT) has evolved as a CT-based daily adaptive treatment. An update of the technical and practical aspects of HDREBT is provided. METHODS AND MATERIALS: Description of technical and practical aspects of HDREBT focused on the preoperative treatment of locally advanced rectal cancer. During preoperative HDREBT, 26 Gy is delivered in four daily applications of 6.5 Gy prescribed to the 100% isodose, covering the clinical target volume. Daily CT scans are obtained and used for plan optimization, leaving patient positioning unchanged between CT scan and treatment delivery. RESULTS: All steps of HDREBT treatment procedure are discussed in detail: flexible proctosigmoidoscopy and clipping; patient setup; applicator placement; target delineation; treatment planning and delivery; and patient care. Afterward, treatment results are reviewed. CONCLUSIONS: CT-based adaptive preoperative HDREBT is a practical and feasible therapy for locally advanced rectal cancer, offering excellent local control with a favorable toxicity profile.

Energy dependent calibration of XR-QA2 radiochromic film with monochromatic and polychromatic x-ray beams.

PURPOSE: This work investigates the energy response and dose-response curve determinations for XR-QA2 radiochromic film dosimetry system used for synchrotron radiation work and for quality assurance in diagnostic radiology, in the range of effective energies 18-46.5 keV. METHODS: Pieces of XR-QA2 films were irradiated, in a plane transverse to the beam axis, with a monochromatic beam of energy in the range 18-40 keV at the ELETTRA synchrotron radiation facility (Trieste, Italy) and with a polychromatic beam from a laboratory x-ray tube operated at 80, 100, and 120 kV. The film calibration curve was expressed as air kerma (measured free-in-air with an ionization chamber) versus the net optical reflectance change (netΔR) derived from the red channel of the RGB scanned film image. Four functional relationships (rational, linear exponential, power, and logarithm) were tested to evaluate the best curve for fitting the calibration data. The adequacy of the various fitting functions was tested by using the uncertainty analysis and by assessing the average of the absolute air kerma error calculated as the difference between calculated and delivered air kerma. The sensitivity of the film was evaluated as the ratio of the change in net reflectance to the corresponding air kerma. RESULTS: The sensitivity of XR-QA2 films increased in the energy range 18-39 keV, with a maximum variation of about 170%, and decreased in the energy range 38-46.5 keV. The present results confirmed and extended previous findings by this and other groups, as regards the dose response of the radiochromic film XR-QA2 to monochromatic and polychromatic x-ray beams, respectively. CONCLUSIONS: The XR-QA2 radiochromic film response showed a strong dependence on beam energy for both monochromatic and polychromatic beams in the range of half value layer values from 0.55 to 6.1 mm Al and corresponding effective energies from 18 to 46.5 keV. In this range, the film response varied by 170%, from a minimum sensitivity of 0.0127 to a maximum sensitivity of 0.0219 at 10 mGy air kerma in air. The more suitable function for air kerma calibration of the XR-QA2 radiochromic film was the power function. A significant batch-to-batch variation, up to 55%, in film response at 120 kV (46.5 keV effective energy) was observed in comparison with published data.

Effective spatially fractionated GRID radiation treatment planning for a passive grid block.

OBJECTIVE: To commission a grid block for spatially fractionated grid radiation therapy (SFGRT) treatments and describe its clinical implementation and verification through the record and verify (R&V) system. METHODS: SFGRT was developed as a treatment modality for bulky tumours that cannot be easily controlled with conventionally fractionated radiation. Treatment is delivered in the form of open-closed areas. Currently, SFGRT is performed by either using a commercially available grid block or a multileaf collimator (MLC) of a linear accelerator. In this work, 6-MV photon beam was used to study dosimetric characteristics of the grid block. We inserted the grid block into a commercially available treatment planning system (TPS), and the feasibility of delivering such treatment plans on a linear accelerator using a R&V system was verified. Dose measurements were performed using a miniature PinPoint(TM) ion chamber (PTW, Freiburg, Germany) in a water phantom and radiochromic film within solid water slabs. PinPoint ion chamber was used to measure the output factors, percentage depth dose (PDD) curves and beam profiles at two depths, depth of maximum dose (zmax) and 10 cm. Film sheets were used to measure dose profiles at zmax and 10-cm depth. RESULTS: The largest observed percentage difference between output factors for the grid block technique calculated by the TPS and measured with the PinPoint ion chamber was 3.6% for the 5 × 5-cm(2) field size. Relatively significant discrepancies between measured and calculated PDD values appear only in the build-up region, which was found to amount to <4%, while a good agreement (differences <2%) at depths beyond zmax was observed. Dose verification comparisons performed between calculated and measured dose distributions were in clinically acceptable agreements. When comparing the MLC-based with the grid block technique, the advantage of treating large tumours with a single field reduces treatment time by at least 3-5 times, having significant impact on patient throughput. CONCLUSION: The proposed method supports and helps to standardize the clinical implementation of the grid block in a safer and more accurate way. ADVANCES IN KNOWLEDGE: This work describes the method to implement treatment planning for the grid block technique in radiotherapy departments.

Delivery validation of an automated modulated electron radiotherapy plan.

PURPOSE: Modulated electron radiation therapy (MERT) represents an active area of interest that offers the potential to improve healthy tissue sparing in treatment of certain cancer cases. Challenges remain however in accurate beamlet dose calculation, plan optimization, collimation method, and delivery accuracy. In this work, the authors investigate the accuracy and efficiency of an end-to-end MERT plan and automated delivery method. METHODS: Treatment planning was initiated on a previously treated whole breast irradiation case including an electron boost. All dose calculations were performed using Monte Carlo methods and beam weights were determined using a research-based treatment planning system capable of inverse optimization. The plan was delivered to radiochromic film placed in a water equivalent phantom for verification, using an automated motorized tertiary collimator. RESULTS: The automated delivery, which covered four electron energies, 196 subfields, and 6183 total MU was completed in 25.8 min, including 6.2 min of beam-on time. The remainder of the delivery time was spent on collimator leaf motion and the automated interfacing with the accelerator in service mode. Comparison of the planned and delivered film dose gave 3%/3mm gamma pass rates of 62.1%, 99.8%, 97.8%, 98.3%, and 98.7% for the 9, 12, 16, and 20 MeV, and combined energy deliveries, respectively. Delivery was also performed with a MapCHECK device and resulted in 3%/3 mm gamma pass rates of 88.8%, 86.1%, 89.4%, and 94.8% for the 9, 12, 16, and 20 MeV energies, respectively. CONCLUSIONS: Results of the authors' study showed that an accurate delivery utilizing an add-on tertiary electron collimator is possible using Monte Carlo calculated plans and inverse optimization, which brings MERT closer to becoming a viable option for physicians in treating superficial malignancies.

Improving the energy response of external beam therapy (EBT) GafChromicTM dosimetry films at low energies (≤ 100 keV).

PURPOSE: Purpose of this work is to investigate the effects of varying the active layer composition of external beam therapy (EBT) GafChromic(TM) films on the energy dependence of the film, as well as try to develop a new prototype with more uniform energy response at low photon energies (⩽ 100 keV). METHODS: First, the overall energy response (S(AD, W)(Q)) of different commercial EBT type film models that represent the three different generations produced to date, i.e., EBT, EBT2, and EBT3, was investigated. Pieces of each film model were irradiated to a fixed dose of 2 Gy to water for a wide range of beam qualities and the corresponding S(AD, W)(Q) was measured using a flatbed document scanner. Furthermore, the DOSRZnrc Monte Carlo code was used to determine the absorbed dose to water energy dependence of the film, f(Q). Moreover, the intrinsic energy dependence, kbq(Q), for each film model was evaluated using the corresponding S(AD, W)(Q) and f(Q). In the second part of this study, the authors investigated the effects of changing the chemical composition of the active layer on SAD, W(Q). Finally, based on these results, the film manufacturer fabricated several film prototypes and the authors evaluated their S(AD, W)(Q). RESULTS: The commercial EBT film model shows an under response at all energies below 100 keV reaching 39% ± 4% at about 20 keV. The commercial EBT2 and EBT3 film models show an under response of about 27% ± 4% at 20 keV and an over response of about 16% ± 4% at 40 keV.S(AD, W)(Q) of the three commercial film models at low energies show strong correlation with the corresponding f(-) (1)(Q) curves. The commercial EBT3 model with 4% Cl in the active layer shows under response of 22% ± 4% at 20 keV and 6% ± 4% at about 40 keV. However, increasing the mass percent of chlorine makes the film more hygroscopic which may affect the stability of the film's readout. The EBT3 film prototype with 7.5% Si shows a significant improvement in the energy response at very low energies compared to the commercial EBT3 films with 4% Cl. It shows under response of 15% ± 5% at about 20 keV to 2% ± 5% at about 40 keV. However, according to the manufacturer, the addition of 7.5% Si as SiO2 adversely affected the viscosity of the active fluid and therefore affected the potential use in commercial machine coating. The latest commercial EBT3 film model with 7% Al as Al2O3 shows an overall improvement in SAD, W(Q) compared to previous commercial EBT3 films. It shows under response at all energies <100 keV, varying from 20% ± 4% at 20 keV to 6% ± 4% at 40 keV. CONCLUSIONS: The energy response of films in the energy range <100 keV can be improved by adjusting the active layer chemical composition. Removing bromine eliminated the over response at about 40 keV. The under response at energies ≤ 30 keV is improved by adding 7% Al to the active layer in the latest commercial EBT3 film models.

Dosimetry of biological irradiations using radiochromic films.

Delivering accurate radiation dose to blood specimens during biological irradiations is essential in quantifying damage of ionizing radiation. To estimate dose to blood samples as accurately as possible, pieces of EBT2 model GAFCHROMIC™ film were placed within an approximately 10 mm finely ground rice layer that was used to simulate test specimens inside 40 mL plastic flasks. Irradiations of flasks were carried out using an X-RAD 320 irradiator with a beam quality of 320 kVp and a measured half value layer of 1.12 mm Cu, in air and in a full scattering setup which consisted of either rice or Solid Water™ (SW) surrounding flasks, filled to the same level at top of the flasks, together with a 5 cm thick SW slab beneath them. Outputs, per cent depth doses and beam profiles at different depths were measured and compared between setups. For the same setting, the dose delivered to the middle flask under the full scattering setup is 22% larger than with the in-air setup at the depth of the specimen and 9.2% more homogeneous across the specimen thickness of 10 mm (2.3% variation in comparison to the surface). Rice showed a fairly similar performance to SW within 1% at the same depth of 10 mm. Experimental setup based on full scattering conditions was shown to provide faster, more homogenous and fairly uniform dose delivery to biological specimens in comparison to conventionally used in-air setups.

SU-E-T-321: Dynamic Modulated Brachytherapy.

PURPOSE: We introduced the concept of Dynamic Modulated Brachytherapy (DMBT) for rectal cancer, last year. To continue our work, we studied different shield designs and investigated the system's tolerance against systematic setup errors. METHODS: As previously presented, our system uses a cylindrical tungsten shield to create a directional radiation profile, which is modulated through translation and rotation using a specialized robotic arm. We used Monte Carlo simulations and an in-house gradient projection optimization algorithm to look at key design parameters. First, we used ideal phantoms to study treatment quality from shield radii ranging 0.5-1.5 cm in 0.25 cm increments. Second, using 36 patient plans, the dependence on radial source position within the shield was studied. We also analyzed the tolerance of the system to systematic setup errors by simulating dose distributions from possible inaccuracies. These included translational and rotational errors as well as possible Ir-192 source misplacements by the afterloading system. RESULTS: Changes in shield radius followed steady patterns. Increasing the radius showed a consistent increase in dose conformality to the tumor volume and better sparing to surrounding tissues. However, there was also a linear increase in total dwell time. There was a trade off to changing the radial position of the source. As the source is brought away from the center, there is a decrease in conformality to the tumor volume, but sparing to healthy tissues was increased and there is a decrease in total dwell time. We found that any potential setup errors for our system, within anticipated margins, had negligible effects on the dose distributions (< 3% deviation). CONCLUSION: Various parameters for shield designs must be balanced for an effective DMBT application. It was found that the system is highly robust against systematic setup uncertainties.

SU-E-T-237: Leading 25 in 25: A Bibliometric Analysis of Classics Articles in IMRT.

PURPOSE: Scientific publication in IMRT has experienced significant development since its introduction. Bibliometric analyses allow an understanding of how this publication trend is organized at an aggregated level. Citation analysis is one of the most widely used bibliometric tools of scientometrics. Analysis of classics, defined as an articles with 100 or more citations, is common in the biomedical sciences as it reflects an article's influence and the recognition it receives in its professional and scientific community. Our objective was to identify the 25 most frequently cited classic articles in IMRT in the past 25 years. METHODS: The 25 most-cited IMRT articles were identified by searching ISI's Web of Knowledge and Pubmed databases for all related publications from 1986 through 2011. Articles were evaluated for several characteristics such as author(s), institution, country of origin, publication year, type, and number of citations. An unadjusted categorical analysis was performed to compare all articles published in the search period. RESULTS: Our search yielded a cumulative total of 37,197 entries for the publication period. Original research and clinical trial articles accounted for 25,827 and 312, respectively, for a total of 25,719 entries. The 25 most-cited articles were identified from the latter sum and selected out of 123 classics. The number of citations per article ranged from 203 to 504. IMRT classics appeared in one general and five core journals. CONCLUSIONS: This study analyzed publication patterns focused on IMRT, its most influential classic articles, journals that published them, their authors and other salient characteristics. Such information is of importance to researchers and those who wish to study the history and development of the field.

High dose rate endorectal brachytherapy as a neoadjuvant treatment for patients with resectable rectal cancer.

In the era of total mesorectal surgery, the issue of radiation toxicity is raised. A novel endocavitary brachytherapy technique was tested as a neoadjuvant treatment for patients with resectable rectal cancer. The objectives of the study were to evaluate the treatment-related toxicity and effects on local recurrence. A dose of 26 Gy was prescribed to the gross tumour volume and intramesorectal deposits seen on magnetic resonance imaging and given over four daily treatments, using the high dose rate delivery system followed by surgery 6-8 weeks later. The study included 93 T3, four T4 and three T2 tumours. Acute proctitis of grade 2 was observed in all patients, but one required transfusion. At a median follow-up time of 60 months, the 5-year actual local recurrence rate was 5%, disease-free survival was 65%, and overall survival was 70%. High dose rate endorectal brachytherapy seems to prevent local recurrence and has a favourable toxicity pattern compared with external beam radiotherapy.

Verification of cell irradiation dose deposition using a radiochromic film.

We describe a technique for the MTT assay that irradiates all cells at once by a combination of couch movement and a step-and-shoot irradiation technique on a linear accelerator with 6 MV and 18 MV photon beams. In two experimental setups, we obtained maximum to minimum dose ranges of 10 for the constant MU/bin (monitor units per bin) setup and 20 for the variable MU/bin technique. The irradiation technique described is dose rate independent and it can be used on any teletherapy irradiation machine. We also employed radiochromic film dosimetry to verify dose delivered in each of the wells within the dish. It is shown that for the lowest doses, relative dose variation within wells reaches a value of 6%. We also demonstrated that the radiochromic film positioned below the 96-well plate does not underestimate dose deposited within each compartment by more than 2% due to the vertical dose gradient.

High dose-rate brachytherapy source position quality assurance using radiochromic film.

Traditionally, radiographic film has been used to verify high-dose-rate brachytherapy source position accuracy by co-registering autoradiographic and diagnostic images of the associated applicator. Filmless PACS-based clinics that do not have access to radiographic film and wet developers may have trouble performing this quality assurance test in a simple and practical manner. We describe an alternative method for quality assurance using radiochromic-type film. In addition to being easy and practical to use, radiochromic film has some advantages in comparison with traditional radiographic film when used for HDR brachytherapy quality assurance.

Accurate skin dose measurements using radiochromic film in clinical applications.

Megavoltage x-ray beams exhibit the well-known phenomena of dose buildup within the first few millimeters of the incident phantom surface, or the skin. Results of the surface dose measurements, however, depend vastly on the measurement technique employed. Our goal in this study was to determine a correction procedure in order to obtain an accurate skin dose estimate at the clinically relevant depth based on radiochromic film measurements. To illustrate this correction, we have used as a reference point a depth of 70 micron. We used the new GAFCHROMIC dosimetry films (HS, XR-T, and EBT) that have effective points of measurement at depths slightly larger than 70 micron. In addition to films, we also used an Attix parallel-plate chamber and a home-built extrapolation chamber to cover tissue-equivalent depths in the range from 4 micron to 1 mm of water-equivalent depth. Our measurements suggest that within the first millimeter of the skin region, the PDD for a 6 MV photon beam and field size of 10 x 10 cm2 increases from 14% to 43%. For the three GAFCHROMIC dosimetry film models, the 6 MV beam entrance skin dose measurement corrections due to their effective point of measurement are as follows: 15% for the EBT, 15% for the HS, and 16% for the XR-T model GAFCHROMIC films. The correction factors for the exit skin dose due to the build-down region are negligible. There is a small field size dependence for the entrance skin dose correction factor when using the EBT GAFCHROMIC film model. Finally, a procedure that uses EBT model GAFCHROMIC film for an accurate measurement of the skin dose in a parallel-opposed pair 6 MV photon beam arrangement is described.

The three-dimensional scintillation dosimetry method: test for a 106Ru eye plaque applicator.

The need for fast, accurate and high resolution dosimetric quality assurance in radiation therapy has been outpacing the development of new and improved 2D and 3D dosimetry techniques. This paper summarizes the efforts to create a novel and potentially very fast, 3D dosimetry method based on the observation of scintillation light from an irradiated liquid scintillator volume serving simultaneously as a phantom material and as a dose detector medium. The method, named three-dimensional scintillation dosimetry (3DSD), uses visible light images of the liquid scintillator volume at multiple angles and applies a tomographic algorithm to a series of these images to reconstruct the scintillation light emission density in each voxel of the volume. It is based on the hypothesis that with careful design and data processing, one can achieve acceptable proportionality between the local light emission density and the locally absorbed dose. The method is applied to a Ru-106 eye plaque immersed in a 16.4 cm3 liquid scintillator volume and the reconstructed 3D dose map is compared along selected profiles and planes with radiochromic film and diode measurements. The comparison indicates that the 3DSD method agrees, within 25% for most points or within approximately 2 mm distance to agreement, with the relative radiochromic film and diode dose distributions in a small (approximately 4.5 mm high and approximately 12 mm diameter) volume in the unobstructed, high gradient dose region outside the edge of the plaque. For a comparison, the reproducibility of the radiochromic film results for our measurements ranges from 10 to 15% within this volume. At present, the 3DSD method is not accurate close to the edge of the plaque, and further than approximately 10 mm (<10% central axis depth dose) from the plaque surface. Improvement strategies, considered important to provide a more accurate quick check of the dose profiles in 3D for brachytherapy applicators, are discussed.