Browsing by Subject "Brachytherapy"

Purpose

Materials and methods

Results/conclusions

Treatment errors can occur in high dose rate (HDR) brachytherapy, but, currently, there is a lack of real-time treatment verification systems that are clinically available and thus many errors are only determined retrospectively, or not at all. Due to the rapid dose fall-off in HDR brachytherapy, small uncertainties can result in large dose variations. These errors can have a large impact on the patient if not detected during the treatment. In-vivo dosimetry is one potential way to detect these errors in real-time. The purpose of this work is to explore further the use of a nano-fiber optic detector (NanoFOD) for real-time dosimetry during HDR brachytherapy treatments. The NanoFOD consists of an inorganic nano-crystalline scintillator fixed on an optical fiber. It is small enough to be placed into clinical catheters and needles, allowing for in-vivo measurements, and is able to measure point doses to sub-millimeter resolution. Previous studies proved the feasibility of using the NanoFOD for real-time measurements in both cylinder and T&O HDR treatments. The purpose of this work is to: (1) determine a way to calibrate the NanoFOD at small source to detector distances, with the end goal to make the NanoFOD usable in more types of HDR deliveries; (2) test the feasibility of using the NanoFOD to measure real-time, in-vivo dose measurements during an US-based HDR prostate phantom end-to-end-test; (3) design and test a novel platform to allow for real time tracking of HDR treatments.

In this thesis a new calibration technique was developed and tested for the calibration of the NanoFOD at short distances from an Ir-192 HDR source. This calibration provides a way to convert the real-time measured voltage to a dose-rate-to-water value for a range of source-to-detector distances, beginning at 0.5 cm, allowing for more accurate dose measurements in HDR brachytherapy applications in which there are typically small volumes, such as prostate HDR, or any other interstitial type implant. Verification of this calibration found accuracy within 7% of the expected cumulative dose values, with a potential uncertainty being the accuracy with which we can position the NanoFOD versus the known location of the source. A second potential uncertainty is the assumption that the entire NanoFOD is water equivalent; when in reality some components are not. Preliminary Monte Carlo simulations were able to determine a relative dose rate value when the NanoFOD material was present, with results indicating the NanoFOD impacts the calculated dose.

This NanoFOD calibration was then used to test the ability of the fiber to take real-time measurements during an HDR prostate phantom end-to-end. Dose differences between the planned and measured cumulative doses when using flexi needles were found to be approximately 18%. This differences between the measured and planned dose values include both uncertainties in the NanoFOD system, as well as US-based HDR prostate brachytherapy workflow uncertainties, and are on the same order of magnitude with other reported in-vivo systems (Mason, Mamo, Al-Qaisieh, Henry, & Bownes, 2016). Through a Type A and Type B uncertainty analysis, the overall uncertainty of the dose measurements achieved by the NanoFOD was determined to be 15.7% and the uncertainty in the measured TPS dose values for HDR prostate treatments was determined to be 15.4%.

For real time tracking of delivered dose during HDR treatments, a novel platform using the NanoFOD detector was designed. The designed prototype interface was successful in displaying in real-time the measured voltage, correctly accounting for background noise, and also automatically detecting the location of the first dwell to start the overlay with the expected signal. When large errors were introduced into a phantom delivery treatment, the interface detected large differences between the measured and expected signals. This platform provides real-time feedback to the user, allowing for in-vivo verification of the dose delivered to the patient, as compared to expected values imported from the TPS. In doing this, the interface has the ability to help identify and reduce potential treatment errors in real-time that could otherwise remain undetected.

Project 1: Chest Phantom Development for Chest X-ray Radiation Protection Surveys

Purpose: Develop an acrylic phantom to accurately represent an average adult’s chest for use in radiographic chest unit radiation protection surveys.

Materials and Methods: 6 sheets of 3.81 cm thick acrylic were cut and assembled to form a 30.5 x 30.5 x 20.3 cm hollow box phantom. The acrylic served as tissue equivalent material and the hollow center simulated lungs in a human patient. Six sheets of 1 mm thick aluminum were cut to line the inner walls of the acrylic phantom to potentially boost scatter radiation. Three phantoms underwent posterior-anterior (PA) and lateral chest protocol radiographic scans: the acrylic phantom (with and without the aluminum lining), a 3 gallon water bottle filled with water, and an adult male anthropomorphic phantom. The phantoms were set up as though they were adult patients and scanned with automatic exposure control. Scatter radiation was measured with ion chamber survey meters at 4 points within the room for each phantom and protocol. The scatter data from the acrylic phantom and water bottle were compared to the anthropomorphic phantom to determine which one more accurately represented an adult patient.

Results: For the PA protocol, the average percent difference in measurements between the acrylic phantom and anthropomorphic phantom was 33.3±28.8% with the aluminum lining and 33.0±21.2% without the lining. The percent difference between the water bottle and anthropomorphic phantom was 66.5±42.0%. For the lateral protocol, the average percent difference in measurements between the acrylic phantom and anthropomorphic phantom was 157.6±5.6% with the aluminum lining and 143.0±17.6% without the lining. The percent difference between the water bottle and anthropomorphic phantom was 78.3±22.8%.

Conclusions: The acrylic phantom provided a more accurate comparison to the anthropomorphic phantom than the water bottle for the PA protocol. For the lateral protocol, neither the acrylic phantom nor water bottle provided an adequate comparison to the anthropomorphic phantom.

Project 2: Internal Beta Dosimetry of an Iodine-131 Labelled Elastin-Like Polypeptide

Purpose: Develop a model and simulation to better understand the dosimetry of an I-131 labeled elastin-like polypeptide (ELP) brachytherapy technique.

Materials and Methods: To develop the model, an average scenario based on mouse trials was explored. A 125 mg tumor was approximated as a sphere, with the I-131 ELP injected into its center. The ELP solidifies into a spherical depot – approximately 1/3 the volume of the tumor – and becomes a permanent brachytherapy source. The injected activity of I-131 was 1.25 mCi. I-131 primarily emits β radiation with an average energy of 182 keV, therefore it was determined that all such emissions were confined within the bounds of the tumor. Gamma emissions associated with I-131 were ignored as they were determined to have enough energy to escape the bounds of the tumor without any interaction. This model was implemented into a simulation using the Monte Carlo program FLUKA. From this simulation, the absorbed dose to the tumor and ELP depot, along with the dose profile, was calculated.

Results: The tumor received an absorbed dose of 72.3 Gy while the ELP received 1.14×10^3 Gy. From the dose profile, it was determined that 99% of the absorbed dose to the tumor was highly localized to a 0.3 mm region surrounding the ELP depot.

Conclusions: The model and simulation provided a better understanding of the dosimetry underlying the novel ELP brachytherapy technique. Results obtained demonstrated that the ELP method delivers doses that are comparable to current conventional brachytherapy techniques.

Project 3: I-131 Beta Detection Using a Scintillating Nanoparticle Detector

Purpose: Determine if a scintillating nanocrystal fiber optic detector (nano-FOD) could detect β emissions from I-131.

Materials and Methods: The nano-FOD’s β response was tested using a source vial containing 101 mCi of I-131 in 2 mL of stabilizing solution. A glass vial containing the I-131 was placed inside a lead pig for shielding. A 1 mm diameter hole was drilled through the tops of the vial and pig to allow insertion of the nano-FOD. Measurements were taken every day over a 17 day period by repeatedly submerging the nano-FOD in the I-131 solution and recording the voltage signal it produced. The activity at the time of measurement was calculated based on the time and date of data acquisition. The net signal and signal-to-noise ratio (SNR) were then calculated and plotted as functions of I-131 concentration.

Results: The nano-FOD produced a measurable response when exposed to the β emissions of I-131. The net signal and SNR both demonstrated a linear correlation with the concentration of I-131.

Conclusions: The nano-FOD was demonstrated to be capable of β detection with a linear correlation to activity. If the signals measured can be calibrated to radiation exposure, then the nano-FOD has promising applications as a novel β detector.

Brachytherapy has emerged as one of the pre-eminent radiotherapy modalities for the treatment of prostate cancer. Current clinical methods utilize titanium encased radioactive seeds that are fixated within the prostate and permanently implanted. A novel brachytherapy alternative that has been developed to improve the delivery of radionuclide intratumorally is the synthetically designed elastin-like polypeptide (ELP). ELP can be injected in fluid form and undergoes an inverse phase transition to a biocompatible coascervate capable of serving as a biocompatible, intratumoral depot. Utilizing a previously developed ELP with a 7 tyrosine C-terminus tail, the therapeutic efficacy of ELP as a radioactive depot for treating prostate cancer was examined in a preclinical, orthotopic model. The orthotopic prostate model was first established by xenografting Bioware® PC-3M-luc-C6 cells into immunoincompetent, Balb/c nude mice. A non-invasive method for tracking tumor progression in vivo was developed using a correlation model comparing quantitative luminescent flux emitted from the cell line against the actual tumor size. The correlation between flux and tumor volume was determined to as Volume = 7.234x10-9x - 18.54, (±21.7%), where x is the supine photon flux measured from a 10 second exposure taken 18 minutes after D-luciferin injection. Radionuclide conjugation of 131I to ELP was conducted using the established IODO-GEN reaction methodology and mice were administered a therapeutic dose of 2mCi / 40µl ELP / 150 mm3 prostate tumor. Intratumoral deposition resulted in tumor regression in 90.9% of treated mice (n=11); 63.6% of which achieved tumor size reduction by over 60%. Radioactivity measurements demonstrate an 89.9% ELP depot retention over 2 weeks. Survival rates of the test group (64%) compared with controls (100%, n=14) indicate further testing is required to optimize radionuclide dosimetry.

The utilization of brachytherapy practice in clinics has been declining over the years. The decline has been linked to a variety of factors including a lack of training opportunities. To improve the quality of intracavitary and interstitial HDR brachytherapy education, a multi-material modular 3D printed pelvic phantom kit prototype simulating normal and cervix pathological conditions has been developed. This comprehensive training phantom is intended to serve as a novel aid in the “300 in 10 Strategy” put forward by the American Brachytherapy Society which calls to train 30 competent brachytherapists per year over the next 10 years.

Patient anatomy was derived from anonymized pelvic CT and MRI scans from different representative patients who had been diagnosed with cervical cancer. The dimensions of patients’ uterine canal sizes and uterine body sizes were measured and used to construct a variety of uteri based off of the averages and standard deviations of the subjects in our study.

The length of the uterine body was measured from top of the fundus to the top of the cervix. The width of the uterine body was measured at the top of the cervix and also measured across the midpoint between the cervix and the fundus. High risk clinical target volumes (HR-CTV) were also extracted from these patients. 3D Slicer (Slicer 4.10.1) was used to import and convert contoured DICOM data into a 3D model. Organs of interest for our prototype include the vaginal canal, uterus, and cervix. A standard rectum, and bladder were also printed.

Individual STL files were imported into Autodesk Meshmixer (3.5.4) and manipulated to include more representative features such as hollowed out cavities and canals. Modular components of the phantom were designed and integrated into patient anatomy using 3D modeling software Shapr3D (Stratasys, 3.35.0).

Flexible and rigid materials were assigned to each component of the phantom. Vero Clear (Stratasys) was assigned to rigid design components including modularity connections. Agilus30 (Stratasys) was assigned to the more flexible components including the vaginal canal, uterus, rectum, and bladder. Each flexible component was assigned a shore hardness value ranging from 30-80 to further individualize the level of flexibility. The finalized prototype was printed using a Stratasys J750 PolyJet printer.

The prototype kit consists of four uteri. The three anteverted uteri in the kit are based on the smallest, the average, and the largest dimensions from our patient set. The fourth uterus is retroverted and uses average dimensions. The four uteri incorporate two embedded HR-CTVs through color staining in the uterine body prints. Four clip-on HR-CTV sections that expand outside the cervix and uterine body are also part of the kit to mimic different pathology. All uterus bodies and the vaginal canal are printed using clear Agilus (shore 30a), and the HR-CTVs are printed externally and into the uterine bodies using a blend of colored Vero and Agilus (shore 40a) as a means of evaluation for tandem/ovoids and needle placement. The bladder surface and rectum are printed in Agilus, shore 35a and 70a, respectively. The outer box was printed using Vero Clear, shore 90. The full kit which consists of an outer box, vulvar entrance, vaginal canal, four uteruses, two embedded HR-CTVs, four clip-on HR-CTVs, a standard bladder, and standard rectum, costs $631 in printing material expenses. This low-cost comprehensive training kit may be used to improve resident comfort in performing gynecological brachytherapy procedures.

Purpose: Clinical brachytherapy systems are capable of delivering very high doses with high dose gradients. It is important therefore to be able to accurately verify the doses calculated by brachytherapy treatment planning. Current dose verification methods are limited by poor resolution, and in the presence of large dose gradients, may give non-­representative results [1]. This thesis aims to evaluate the feasibility of a novel radiochromic dosimetry system for in-­vivo dose verification in organs at risk (bladder and rectum) in high dose rate (HDR) intracavitary gynecological brachytherapy through a comparison with a gold standard.

Methods: A novel dosimeter PRESAGE®-­IV designed for in-­vivo dosimetry is investigated. PRESAGE®-­IV dosimeters are small cylinders 4mm in diameter by 20mm in height. When irradiated, the dosimeters change color in proportion to the local absorbed dose. The dosimeters were irradiated to doses between 1-­15 Gy. Two methods were investigated for readout of this radiochromic response: (i) a volume averaged readout by conventional spectrophotometer, and (ii) a line profile readout by a novel 2D projection imaging method utilizing a high-­resolution (50 micron) telecentric optical system. Method (i) is considered the gold standard, as it is has been extensively used with PRESAGE® in well-­defined optical-­cuvettes. The feasibility of PRESAGE®-­IV was evaluated by comparison to standard PRESAGE® in optical-­cuvettes. The feasibility of the high-­resolution readout (method ii) was evaluated by direct comparison against method (i). Dosimeters were also tested in-­vivo on six patients undergoing Iridium-­192 HDR intracavitary brachytherapy treatments and dose measurements were compared to Eclipse Treatment Planning System (Varian Medical Systems).

Results: When compared to the gold standard (optical-­cuvettes), the sensitivity and noise of PRESAGE®-­IV shows a linear relationship in sensitivity between 1-­15 Gy with a 95% confidence interval in the slope (0.8703 +/-­ 0.0192). The feasibility of the high-­resolution readout (method ii) evaluated by direct comparison against method (i) resulted in a sensitivity of 0.0136 ± 0.0002 and for the spectrophotometer 0.0135 ± 0.0002, which is a 0.74% difference in sensitivity within the 95% confidence interval. Examination of patient data showed large differences, and on average gave 19% and 22% differences in measured doses vs. Eclipse measurements in the bladder and rectum, respectively.

Conclusions: Results show that a novel radiochromic dosimetry system for in-­vivo dose verification in organs at risk is feasible. The conventional spectrophotometer readout method had the limitation that it averages the change in optical density over a 10 mm area of the dosimeter. The novel, high-­resolution 2D readout technique was found to have the advantage of producing images that could be further analyzed through line profiles in any area of the dosimeter. Due to the large differences in measured doses for organs at risk, further work is needed to validate dosimeter-­positioning technique.

The thesis has two parts. The first project relates to real time dosimetry in Gynecological (GYN) High Dose Rate (HDR) Brachytherapy Treatments and the second part investigates a new workflow for Image Guided Brachytherapy (IGBT) for centers that do not have access to MRI with applicator in-situ.

Project 1: Real-time Dosimetry in HDR Brachytherapy using the Duke designed NanoFOD dosimeter: Limits of Error Detection in Clinical Applications

Purpose: Previously, an optical fiber radiation detector system was shown to be capable of identifying potential high dose rate (HDR) brachytherapy delivery errors in real time. The purpose of this work is to determine this detector’s limits of error detection in vaginal cylinder and tandem and ovoid-type HDR gynecological brachytherapy treatments.

Method and Materials: The system consists of a scintillating nanoparticle-terminated fiber-optic dosimeter (NanoFOD) and a LabView platform (Versions 2015 and 2017; National Instruments Corporation, Austin, TX) which displays the real-time voltages measured by the NanoFOD during HDR treatment delivery. The platform allows for the measured voltage to be overlaid on the expected detector signal. To test the limitation of error detectability in vaginal cylinder brachytherapy, the NanoFOD was taped 1.5-cm from the tip of a 3-cm diameter Varian manufactured stump cylinder. This setup was

imaged using CT to localize the NanoFOD, and a plan was generated based on one of the institutional 3-cm stump cylinder templates with 9 dwell positions. For each dwell position, the expected voltage and doses were calculated using the dose distribution exported from the treatment planning system (TPS), a previously obtained distance-based calibration curve for the NanoFOD and TG-229 along and away table. The voltage values were imported to the LabView for real time monitoring. With a known location of the NanoFOD tip, the expected doses from the NanoFOD at each dwell position were calculated for all applicators for: 1) the clinical plan; 2) wrong source guide tube (SGT); 3) wrong cylinder; 4) wrong treatment template; 5) wrong step size, as well as 6) incorrect positioning of the cylinder insert. Measurements of voltage from each delivered plan were converted to dose per dwell and compared to the expected dose values.

In addition to experiments, a simulation-based limit of error detection with cylinder was studied and the results obtained from simulation were compared to experimental results. Simulation was done by modifying the applicator parameters and the incorrect plans were generated for 1) wrong SGT lengths 5-mm to 70-mm longer than correct length with a 5-mm interval; 2) wrong cylinder; 3) wrong treatment template; 4) wrong step size, as well as 5) incorrect positioning of the cylinder insert. Doses per dwell were also calculated and compared to the doses from correct plan.

Furthermore, simulations-only for T&O plans were also performed. Two representative clinical T&O-based plans with extra needles were used to establish the simulation-based limits of error detectability of the NanoFOD system. With a known location of the NanoFOD tip, the expected doses from the NanoFOD at each dwell position were calculated for all applicators for: 1) the clinical plan; 2) wrong treatment lengths (TL); 3) wrong connection to afterloader; 4) wrong digitization direction; and 5) wrong step size.

From previous work, it has been determined that the overall uncertainty in dose of this system in HDR brachytherapy is 20%. The percent difference (PD) between expected and measured doses and, between the simulated doses from correct and incorrect plans was calculated and compared to 20% to determine if a certain potential error can be detected with the NanoFOD system.

Results: For the cylinder experiments, when the correct treatment was delivered, the median PD over 9 dwells between measured and expected dose from each dwell was 11%. When the wrong SGT, wrong cylinder size, or wrong clinical template was used, the system detected PD values of -91.6%, -71.4% and -29.6% at the first dwell. With wrong step, the system showed large discrepancies starting at the third dwell position (58.6%). When incorrect cylinder insert length was 0.5cm, 1.0cm and 1.5cm, the significant PD values captured were -29.4%, -28.1% and -22.5% at 3rd, 2nd and 1st dwell, respectively.

In TPS simulations for the cylinder applicator, PD from wrong SGT, wrong cylinder size and wrong template and were -93.6%, -90.8% and -57.8% at first dwell. For wrong step size, the simulation predicted the PD to be greater than 20% (47.2%) starting at first dwell. For all incorrect insert length, simulation predicted greater than 20% PD (-38.6%, -34.9%, -38.6%) at first dwell. For incorrect SGT lengths range from 5mm to 70mm, simulation-based PD was from -28.0% to -82.3% at the first dwell, indicating the NanoFOD caught this error when the SGT was only 5-mm longer.

In TPS simulations with two T&O-based plans, with incorrect treatment length (TL, 5mm-70mm), the PD ranges for the two patients were 26.4%-26.8%, 20.4%-30.9%, and 30.9%-57% in 10mm TL tandem, 5mm TL ovoid and 10mm TL needle at first dwell. PD values were -44.1% to -36.4%, -75.3% to 96.4%, and -39.6% to 298.1% respectively at the first dwell when connections between tandem and left ovoid, left needle and left ovoid, left needle and tandem were swapped. When the two needles were switched, PD values were 43.1% and 63.6% at the 1st and 3rd dwell for patient A and patient B. Switching connection between the two ovoids did not produce significant PD for patient A because the two ovoids were identically loaded. For patient B, the PD was 87.5% when ovoids were swapped. Incorrect direction of digitization made the signal too low to be detected, an indication that treatment should be stopped. With wrong step size in tandem, ovoid and needle, simulation-based PD range in dose for two patients were 25.8%-34.9%, 34.3%-37.4%, and 20.7%-81.5%, respectively at 3rd, 2nd and 1st dwell for both patients.

Conclusion:

Using the 20% error detection threshold, the NanoFOD system was able to detect errors in real time cylinder tests when the wrong cylinder size, wrong SGT and wrong template were used, all at the first dwell position. For subtle errors such as small incorrect catheter insertions, the real-time system can detect errors starting with the second or third dwell position. The Labview interface is a good tool to use for real time tracking of the delivery.

TPS simulation predicted comparable discrepancies to PD obtained from experimental measurements when wrong cylinder size and wrong source guide tube was used. The disagreement between simulation-based PD and experiment-based PD is due to uncertainty in positioning during the experiment, as the nanoFOD in current form does not have a radio opaque marker to help with easy identification. TPS simulation was thus used for more complex applicators, knowing that simulations and experiments match.

With the 20% PD as an indication of wrong treatment in T&O-based HDR cases, the NanoFOD can capture all simulated gross errors within the first few dwells into the treatment, indicating it is capable of real-time verification of T&O HDR brachytherapy. Although the two T&O plans were different, the NanoFOD was able to capture the errors at similar dwell positions regardless of the difference in planning. Overall, the NanoFOD can catch, in real time, potential gross errors in clinical HDR.

Project 2: Investigation of Contour-based Deformable Image Registration (cbDIR) of pre-brachytherapy MRI (pbMRI) for target definition in HDR cervical cancer treatments

Purpose: While MRI-guided brachytherapy has been considered the gold standard for IGBT treatment for cervical cancer, practical factors such as cost, MRI access and clinical flow efficiency have limited the use of MRI for brachytherapy treatments. However, a pre-brachytherapy MRI (pbMRI) is usually taken before the brachytherapy to assess the tumor regression after external beam treatments. The purpose of this project is to investigate the role of contour-based deformable image registration of the pbMRI in target definition for high dose rate (HDR) cervical cancer treatments.

Method and Materials: Thirty-five patients with locally advanced cervical cancer treated at Duke University with Tandem and Ovoids (T&O) applicators were studied. A pbMRI was acquired for all patients. Each patient also had MRI and CT taken with applicator in situ at the time of the first fraction. The uterus structure contoured on pbMRI was deformed using contour-based (cb) and hybrid contour-based (hcb) DIR to the same structure contoured on the CT of first HDR fraction (MIM Software Inc., v 6.7.3 and v 6.8.11). The deformation matrix was used to deform the dHRCTV, which was then compared with the ground truth HRCTV (gtHRCTV) obtained on the MRI of 1st HDR fraction. Dice Similarity Coefficients (DSC) and Hausdorff Distance (med_HD, max_HD) were used to evaluate the overlap and mismatch at boundaries between the deformed HRCTV and gtHRCTV using both DIR methods. The process of generating dHRCTV requires user’s manual input. Therefore, inter- and intra-user variability using cbDIR, as well as the difference in the two DIR methods were investigated.

Results: The pbMRI scan was acquired on average 5.9+/-3.8 days before first HDR fraction. Median DSC for uterus was 0.9 (IQR 0.88-0.93) and 0.93 (IQR 0.92-0.94), and for HRCTV was 0.64 (IQR 0.52-0.71) and 0.68 (IQR 0.59-0.72) for cbDIR and hcbDIR, respectively. The median med_HD for uterus was 0.09cm (IQR 0.08-0.1cm) and 0.08cm (IQR 0.06-0.09cm). The median max_HD for HRCTV was 1.37cm (IQR 1.1-2.3cm) and 1.39cm (IQR 1.1-1.6cm) with cbDIR and hcbDIR respectively. Limited inter-user, intra-user, and DSC variability between DIR versions were found (p=0.53, p=0.77, p=0.18, respectively).

Conclusion: Contour-based DIR based on uterus/cervix structure is proven to be relatively user independent, improves when hybrid contoured based DIR algorithms are used, and is expected to serve as a good starting point for HRCTV definition for HDR planning in the absence of MRI with applicators in-situ.

Intratumoral radiation therapy – ‘brachytherapy’ – is a highly effective treatment for solid tumors, particularly prostate cancer. Current titanium seed implants, however, are permanent and are limited in clinical application to indolent malignancies of low- to intermediate-risk. Attempts to develop polymeric alternatives, however, have been plagued by poor retention and off-target toxicity due to degradation.

Herein, we report on a new approach whereby thermally sensitive micelles composed of an elastin-like polypeptide (ELP) are labeled with the radionuclide 131-Iodine to form an in situ hydrogel that is stabilized by two independent mechanisms: first, body heat triggers the radioactive ELP micelles to rapidly phase transition into an insoluble, viscous coacervate in under 2 minutes; second, the high energy β-emissions of 131-Iodine further stabilize the depot by introducing crosslinks within the ELP depot over 24 hours. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3M-luc-C6 prostate tumor and a human BxPc3-luc2 pancreatic tumor model. The ELP depots retained greater than 52% and 70% of their radioactivity through 60 days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (≤ 0.1% ID) in off-target tissues after 72 hours. The 131I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60 days compared to 12 days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p = 0.001, ANOVA) and enhanced median survival to 27 days over controls.

We then demonstrated that 131I-ELP brachytherapy can work synergistically with paclitaxel chemotherapy to overcome the intrinsic resistance found in pancreatic tumors. Treating tumors with an optimized radioactivity dose of 10.0 µCi/mg and systemically administered paclitaxel nanoparticles achieved complete regression in BxPc3-luc2, MIA PaCa-2, and AsPc-1 tumor models. Moreover, responses occurred irrespective of the paclitaxel dose (between 12.5-50 mg/kg) or the formulation (Abraxane or micelle formulation). A comparative study utilizing an aggressive 5x 5Gy hypofractionated X-ray radiation produced only minor growth inhibition, with or without paclitaxel.

The mechanistic underpinnings of this effect were explored in an orthotopic model to reveal the fundamental differences between 131I-ELP therapy and conventional radiotherapy. Continuous dose exposure was found to coordinate much more effectively with the temporal sensitization mechanisms of paclitaxel, as evidenced by TUNEL immunohistochemistry. Stromal collagen and cellular junctional proteins regulating interstitial permeability (Claudin-4, CD31, and VE-Cadherin) were dysregulated after 131I-ELP treatment. Fluorescent analysis of paclitaxel nanoparticles revealed significantly higher paclitaxel accumulation in brachytherapy tumors after treatment (p<0.01). These results show that 131I-ELP biopolymer brachytherapy offers a highly attractive alternative to current radiotherapy techniques and demonstrated negligible toxicity.

MR-based planning provides many benefits to planning of the HDR brachytherapy component of treatments for cervical cancer patients but requires the acquisition of different imaging sets that need to be registered for planning. However, registration between images introduces unknown uncertainties which impact the dose metrics that are essential to assessing brachytherapy plans. The goal of this project is to determine the overall effects of uncertainties in image registration between 1) T1- and T2-weighted MR images, and 2) planning CT and T1-weighted MR. The study looks at a total of 60 treatment fractions from thirteen patients for tandem and ovoid treatments. Workflows were created to compare clinical registrations with an automated intensity-based registration. In evaluating the overall uncertainty budget due to registration, the two different contour sets from the two different registrations were compared by calculation of the percent differences in important dosimetric values for the treatment target and also organs at risk. The data collected show that for both T1-MR to T2-MR and T1-MR to CT registration the average deviation for the target was very close to 0 with a reasonable tight standard deviation within 3%. However, the average deviation for organs at risk is greater which may mean patients are receiving more dose to those organs at risk than indicated due to uncertainties of registration caused by shifts and deformation between CT and T1- and T2-weighted MR.

The purpose of this research is to validate the use of a PRESAGE dosimeter as a method to quantitatively measure dose distributions of injectable brachytherapy based on elastin-like polypeptide (ELP) nanoparticles. ELP has several useful properties for treatment purposes, including the ability to be tagged with a radioactive element, an inverse temperature phase transition useful for self-assembly into hydrophobic aggregation upon injection, and a highly tunable threshold temperature based on the amino acid composition and concentration. PRESAGE is a solid, transparent polyurethane-based dosimeter whose dose is proportional to a change in optical density, making it useful for visualizing the dose from a radionuclide-tagged-ELP injection. Initial experiments with the gel phantoms demonstrate viability for assessing I-125 dose deposition, as the image analysis showed the similar relative dose distributions compared with a MATLAB simulation.