Determining optimal eluter design by modeling physical dose enhancement in brachytherapy.

PURPOSE: In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio. MATERIALS AND METHODS: The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125 I permanent prostate implants. Compound concentrations were calculated using steady-state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (ϕb ). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat ). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion-elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other. RESULTS: The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3 , ϕb from 0.01 to 4 mm-1 , csat from 0.05 to 7.5 times the steady-state compound concentration released from the surface of the eluter. The number of used eluters (ne ) was simulated from 10 to 60 eluters. For the region of (csat , Φ)-space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (csat , Φ)-space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations. CONCLUSIONS: Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.

Real-time inverse high-dose-rate brachytherapy planning with catheter optimization by compressed sensing-inspired optimization strategies.

This paper demonstrates that optimization strategies derived from the field of compressed sensing (CS) improve computational performance in inverse treatment planning (ITP) for high-dose-rate (HDR) brachytherapy. Following an approach applied to low-dose-rate brachytherapy, we developed a reformulation of the ITP problem with the same mathematical structure as standard CS problems. Two greedy methods, derived from hard thresholding and subspace pursuit are presented and their performance is compared to state-of-the-art ITP solvers. Applied to clinical prostate brachytherapy plans speed-up by a factor of 56-350 compared to state-of-the-art methods. Based on a Wilcoxon signed rank-test the novel method statistically significantly decreases the final objective function value (p < 0.01). The optimization times were below one second and thus planing can be considered as real-time capable. The novel CS inspired strategy enables real-time ITP for HDR brachytherapy including catheter optimization. The generated plans are either clinically equivalent or show a better performance with respect to dosimetric measures.

Comprehensive quality assurance phantom for the small animal radiation research platform (SARRP).

PURPOSE: To develop and test the suitability and performance of a comprehensive quality assurance (QA) phantom for the Small Animal Radiation Research Platform (SARRP). METHODS AND MATERIALS: A QA phantom was developed for carrying out daily, monthly and annual QA tasks including: imaging, dosimetry and treatment planning system (TPS) performance evaluation of the SARRP. The QA phantom consists of 15 (60 × 60 × 5 mm(3)) kV-energy tissue equivalent solid water slabs. The phantom can incorporate optically stimulated luminescence dosimeters (OSLD), Mosfet or film. One slab, with inserts and another slab with hole patterns are particularly designed for image QA. RESULTS: Output constancy measurement results showed daily variations within 3%. Using the Mosfet in phantom as target, results showed that the difference between TPS calculations and measurements was within 5%. Annual QA results for the Percentage depth dose (PDD) curves, lateral beam profiles, beam flatness and beam profile symmetry were found consistent with results obtained at commissioning. PDD curves obtained using film and OSLDs showed good agreement. Image QA was performed monthly, with image-quality parameters assessed in terms of CBCT image geometric accuracy, CT number accuracy, image spatial resolution, noise and image uniformity. CONCLUSIONS: The results show that the developed QA phantom can be employed as a tool for comprehensive performance evaluation of the SARRP. The study provides a useful reference for development of a comprehensive quality assurance program for the SARRP and other similar small animal irradiators, with proposed tolerances and frequency of required tests.

Balancing dose and image registration accuracy for cone beam tomosynthesis (CBTS) for breast patient setup.

PURPOSE: To balance dose reduction and image registration accuracy in breast setup imaging. In particular, the authors demonstrate the relationship between scan angle and dose delivery for cone beam tomosynthesis (CBTS) when employed for setup verification of breast cancer patients with surgical clips. METHODS: The dose measurements were performed in a female torso phantom for varying scan angles of CBTS. Setup accuracy was measured using three registration methods: Clip centroid localization accuracy and the accuracy of two semiautomatic registration algorithms. The dose to the organs outside of the ipsilateral breast and registration accuracy information were compared to determine the optimal scan angle for CBTS for breast patient setup verification. Isocenter positions at the center of the patient and at the breast-chest wall interface were considered. RESULTS: Image registration accuracy was within 1 mm for the CBTS scan angles theta above 20 degrees for some scenarios and as large as 80 degrees for the worst case, depending on the imaged breast and registration algorithm. Registration accuracy was highest based on clip centroid localization. For left and right breast imaging with the isocenter at the chest wall, the dose to the contralateral side of the patient was very low (<0.5 cGy) for all scan angles considered. For central isocenter location, the optimal scan angles were 30 degrees - 50 degrees for the left breast imaging and 40 degrees - 50 degrees for the right breast imaging, with the difference due to the geometric asymmetry of the current clinical imaging system. CONCLUSIONS: The optimal scan angles for CBTS imaging were found to be between 10 degrees and 50 degrees, depending on the isocenter location and ipsilateral breast. Use of the isocenter at the breast-chest wall locations always resulted in greater accuracy of image registration (<1 mm) at smaller angles (10 degrees - 20 degrees) and at lower doses (<0.1 cGy) to the contralateral organs. For chest wall isocenters, doses delivered to organs outside of the target breast were much smaller than the scattered and leakage doses of the treatment beams. The complete volumetric information of all clips in the region of interest, combined with the small dose to the contralateral organs and the small scan angle, could result in an advantage for small angle CBTS with off center isocenters over simple orthogonal pairs.

Radiosensitizer-eluting nanocoatings on gold fiducials for biological in-situ image-guided radio therapy (BIS-IGRT).

Image-guided radiation treatments (IGRT) routinely utilize radio-opaque implantable devices, such as fiducials or brachytherapy spacers, for improved spatial accuracy. The therapeutic efficiency of IGRT can be further enhanced by biological in situ dose painting (BIS-IGRT) of radiosensitizers through localized delivery within the tumor using gold fiducial markers that have been coated with nanoporous polymer matrices loaded with nanoparticles (NPs). In this work, two approaches were studied: (i) a free drug release system consisting of Doxorubicin (Dox), a hydrophilic drug, loaded into a non-degradable polymer poly(methyl methacrylate) (PMMA) coating and (ii) poly(d,l-lactic-co-glycolic acid) (PLGA) NPs loaded with fluorescent Coumarin-6, serving as a model for a hydrophobic drug, in a biodegradable chitosan matrix. Temporal release kinetics measurements in buffer were carried out using fluorescence spectroscopy. In the first case of free Dox release, an initial release within the first few hours was followed by a sustained release over the course of the next 3 months. In the second platform, release of NPs and the free drug was controlled by the degradation rate of the chitosan matrix and PLGA. The results show that dosage and rate of release of these radiosensitizers coated on gold fiducials for IGRT can be precisely tailored to achieve the desired release profile for radiation therapy of cancer.

GAF film dosimetry of a tandem positioned beta-emitting intravascular brachytherapy source train.

Coronary artery brachytherapy may require treatment of lesions longer than a single source length. A treatment option is tandem positioning of the single source. This study presents relative dosimetric measurements of a cardiovascular brachytherapy source and the dosimetric characteristics in the junction region of tandem treatments. Measurements were carried out using a Novoste Beta Cath 90Sr/90Y 40 mm beta source in a plastic water phantom. Radiochromic MD-55-2 film, calibrated using both 6 MV photon and 6 MeV electron beams from a linear accelerator, was used as the dosimeter. Dose distributions around a single source and in the junction region of tandem irradiation were measured. Measurements of the near field dose as close as 1.2 mm from the source are presented. Significant over- or underdoses in the junction region of tandem irradiation were quantified. At a radial distance of 2 mm from the longitudinal axis of the source, the dose value in the middle of the junction region, normalized to the dose at 2 mm midline single source, was about 182% for a 2-seed overlap and 16% for a 2-seed gap, respectively. Dose distributions in the junction region as a function of source overlap and radial distance have fairly high gradients and exhibit characteristic patterns. The fraction of prescription dose was found to have a sigmoidal dependence on overlap size, for radial distances ranging between 1.2 and 3 mm. The parameters of these sigmoids, quantified as functions of radial distance, could be used to provide quick and reasonable over/underdose estimates, given any potential overlap or gap in the junction area, with an uncertainty within 10%.

Intraoperative planning and evaluation of permanent prostate brachytherapy: report of the American Brachytherapy Society.

PURPOSE: The preplanned technique used for permanent prostate brachytherapy has limitations that may be overcome by intraoperative planning. The goal of the American Brachytherapy Society (ABS) project was to assess the current intraoperative planning process and explore the potential for improvement in intraoperative treatment planning (ITP). METHODS AND MATERIALS: Members of the ABS with expertise in ITP performed a literature review, reviewed their clinical experience with ITP, and explored the potential for improving the technique. RESULTS: The ABS proposes the following terminology in regard to prostate planning process: *Preplanning--Creation of a plan a few days or weeks before the implant procedure. *Intraoperative planning--Treatment planning in the operating room (OR): the patient and transrectal ultrasound probe are not moved between the volume study and the seed insertion procedure. * Intraoperative preplanning--Creation of a plan in the OR just before the implant procedure, with immediate execution of the plan. *Interactive planning--Stepwise refinement of the treatment plan using computerized dose calculations derived from image-based needle position feedback. *Dynamic dose calculation--Constant updating of dose distribution calculations using continuous deposited seed position feedback. Both intraoperative preplanning and interactive planning are currently feasible and commercially available and may help to overcome many of the limitations of the preplanning technique. Dosimetric feedback based on imaged needle positions can be used to modify the ITP. However, the dynamic changes in prostate size and shape and in seed position that occur during the implant are not yet quantifiable with current technology, and ITP does not obviate the need for postimplant dosimetric analysis. The major current limitation of ITP is the inability to localize the seeds in relation to the prostate. Dynamic dose calculation can become a reality once these issues are solved. Future advances can be expected in methods of enhancing seed identification, in imaging techniques, and in the development of better source delivery systems. Additionally, ITP should be correlated with outcome studies, using dosimetric, toxicity, and efficacy endpoints. CONCLUSION: ITP addresses many of the limitations of current permanent prostate brachytherapy and has some advantages over the preplanned technique. Further technologic advancement will be needed to achieve dynamic real-time calculation of dose distribution from implanted sources, with constant updating to allow modification of subsequent seed placement and consistent, ideal dose distribution within the target volume.

A practical method to achieve prostate gland immobilization and target verification for daily treatment.

PURPOSE: A practical method to achieve prostate immobilization and daily target localization for external beam radiation treatment is described. METHODS AND MATERIALS: Ten patients who underwent prostate brachytherapy using permanent radioactive source placement were selected for study. To quantify prostate motion both with and without the presence of a specially designed inflatable intrarectal balloon, the computerized tomography-based coordinates of all intraprostatic radioactive sources were compared over 3 consecutive measurements at 1-min intervals. RESULTS: The placement and inflation of the intrarectal balloon were well tolerated by all patients. The mean (range) displacement of the prostate gland when the intrarectal balloon was present vs. absent was 1.3 (0-2.2) mm vs. 1.8 (0-9.1) mm (p = 0.03) at 2 min respectively. The maximum displacement in any direction (anterior-posterior, superior-inferior, or right-left) when the intrarectal balloon was inflated vs. absent was reduced to < or =1 mm from 4 mm. CONCLUSIONS: Both prostate gland immobilization and target verification are possible using a specially designed inflatable intrarectal balloon. Using this device, the posterior margin necessary on the lateral fields to ensure dosimetric coverage of the entire prostate gland could be safely reduced to 5 mm and treatment could be set up and verified using a lateral portal image.

Evaluation of three-dimensional finite element-based deformable registration of pre- and intraoperative prostate imaging.

In this report we evaluate an image registration technique that can improve the information content of intraoperative image data by deformable matching of preoperative images. In this study, pretreatment 1.5 tesla (T) magnetic resonance (MR) images of the prostate are registered with 0.5 T intraoperative images. The method involves rigid and nonrigid registration using biomechanical finite element modeling. Preoperative 1.5 T MR imaging is conducted with the patient supine, using an endorectal coil, while intraoperatively, the patient is in the lithotomy position with a rectal obturator in place. We have previously observed that these changes in patient position and rectal filling produce a shape change in the prostate. The registration of 1.5 T preoperative images depicting the prostate substructure [namely central gland (CG) and peripheral zone (PZ)] to 0.5 T intraoperative MR images using this method can facilitate the segmentation of the substructure of the gland for radiation treatment planning. After creating and validating a dataset of manually segmented glands from images obtained in ten sequential MR-guided brachytherapy cases, we conducted a set of experiments to assess our hypothesis that the proposed registration system can significantly improve the quality of matching of the total gland (TG), CG, and PZ. The results showed that the method statistically-significantly improves the quality of match (compared to rigid registration), raising the Dice similarity coefficient (DSC) from prematched coefficients of 0.81, 0.78, and 0.59 for TG, CG, and PZ, respectively, to 0.94, 0.86, and 0.76. A point-based measure of registration agreement was also improved by the deformable registration. CG and PZ volumes are not changed by the registration, indicating that the method maintains the biomechanical topology of the prostate. Although this strategy was tested for MRI-guided brachytherapy, the preliminary results from these experiments suggest that it may be applied to other settings such as transrectal ultrasound-guided therapy, where the integration of preoperative MRI may have a significant impact upon treatment planning and guidance.

Estimating deaths from industrial injury by capture-recapture: a cautionary tale.

BACKGROUND: Capture-recapture methods are increasingly being used to improve surveillance for a number of diseases. However, concerns persist regarding the validity of estimates obtained. METHOD: Capture-recapture methods were applied to estimate the ability of four separate data sources on occupational fatalities to predict the 237 deaths ('gold standard') we determined from a special in-depth study of medical examiner records. RESULTS AND CONCLUSION: Capture-recapture results based upon the four sources vary according to different models. However, both separately and in aggregate of industry type and cause of death, most models seriously underestimate the gold standard, and give a misleading impression of precision of the estimate of hidden individuals. It is commonly believed that reliable estimates from such methods require lists with high coverage and parsimonious models. Here, to obtain an estimate consistent with the gold standard, the list with almost complete coverage must be discarded and a complex model fitted. It is argued that this conclusion is of widespread application.

Optimizing target coverage by dosimetric feedback during prostate brachytherapy.

PURPOSE: Postimplant dosimetry of permanent prostate implants shows a loss of coverage compared to the preplan. One contributing factor is needle misplacement. The significance of needle misplacement and the clinical utility of dosimetric feedback were analyzed in the setting of interventional magnetic resonance (IMR) guided prostate brachytherapy. METHODS AND MATERIALS: Information provided by an intraoperative planning system was analyzed for 10 patients. Needle misplacement was measured and the dosimetric consequences calculated. Additional catheters and sources were placed following the insertion of all planned catheters to compensate for nonideal needle placement. RESULTS: Source misplacement ranged from 0.0 to 1.0 cm (median, 0.3 cm). The resulting loss of coverage ranged from 1% to 13%, and the intraoperative dosimetric feedback allowed a recovery of from 0% to 12% coverage. Between 0 and 3 (median, 2) additional needles and from 0 to 10 (median, 8) additional sources were required to restore coverage of the target. Final planned coverage exceeded 94% for all patients. CONCLUSION: The discrepancy between planned and achieved needle placement leads to a loss of dosimetric coverage of the target volume. Dosimetric feedback allows compensation for needle divergence. The technique of real-time dosimetric feedback does not require an IMR system, and could be generalized to ultrasound-guided implants.

Feasibility of transperineal prostate biopsy under interventional magnetic resonance guidance.

A patient, who was not suited for ultrasound-guided biopsy, was biopsied in an interventional magnetic resonance unit at Brigham and Women's Hospital. Real-time magnetic resonance imaging provided verification of placement before tissue samples were taken. This technique successfully sampled tissue from the prostate and led to a diagnosis of cancer.

Transperineal magnetic resonance image guided prostate biopsy.

PURPOSE: We report the findings of a transperineal magnetic resonance image (MRI) guided biopsy of the prostate in a man with increasing prostate specific antigen who was not a candidate for a transrectal ultrasound guided biopsy. MATERIALS AND METHODS: Using an open configuration 0.5 Tesla MRI scanner and pelvic coil, a random sextant sample was obtained under real time MRI guidance from the peripheral zone of the prostate gland as well as a single core from each MRI defined lesion. The patient had previously undergone proctocolectomy for ulcerative colitis and, therefore, was not a candidate for transrectal ultrasound guided biopsy. Prior attempts to make the diagnosis of prostate cancer using a transurethral approach were unsuccessful. RESULTS: The random sextant samples contained benign prostatic hyperplasia, whereas Gleason grade 3 + 3 = 6 adenocarcinoma was confirmed in 15% and 25% of the 2 cores obtained from the MRI targeted specimens of 2 defined lesions. The procedure was well tolerated by the patient. CONCLUSIONS: Transperineal MRI guided biopsy is a new technique that may be useful in detecting prostate cancer in men with increasing prostate specific antigen who are not candidates for transrectal ultrasound guided biopsy.

Real-time magnetic resonance imaging-guided brachytherapy in the treatment of selected patients with clinically localized prostate cancer.

BACKGROUND AND PURPOSE: A real-time three-dimensional magnetic resonance imaging (MRI)-guided implant technique has been designed and implemented. This report summarizes the dosimetry achieved and the acute morbidity in the first patients. PATIENTS AND METHODS: To date, 43 patients with clinical stage T(1c)N(X)M(0) prostate cancer, serum prostate specific antigen <10 ng/mL, and biopsy Gleason score no higher than 3 + 4 have been treated. The procedure was performed using an open magnet, with axial T1-weighted and fast spin echo images. The prescribed minimum radiation dose to the peripheral zone was 160 Gy. The total activity implanted ranged from 18.8 to 47.5 mCi using 43 to 120 (median 80) (125)I seeds. Dosimetric analyses were performed intraoperatively in real time for the tumor, anterior rectal wall, and prostatic urethra. RESULTS: The percent of the clinical target volume receiving the prescription dose was 89% to 99% (median 96%). Using a conservative estimate of 164 Gy, no more than 9% of the urethral volume exceeded the tolerated dose. Using an estimated tolerated dose of 82 Gy, 30% to 100% (median 68%) of the anterior rectal wall volume was within the dose limit. Thirty-nine patients voided spontaneously within 3 hours of Foley catheter discontinuation, although four patients required recatheterization for a period. No patient reported gastrointestinal or sexual dysfunction during the first postoperative month. CONCLUSION: A real-time MR-guided technique can achieve a minimum of 89% coverage of the tumor volume while maintaining the prostatic urethra and most of the anterior rectal wall below tolerance levels. Acute morbidity was minimal. Further follow-up is needed to ascertain the impact on cancer control and quality of life.