Photodynamic Therapy (PDT) has proven to be a minimally invasive alternative treatment option for various conditions including cancer. The treatment efficacy of deep-seated tumours with PDT is variable, compared to the treatment of tissue surfaces such as the skin and esophagus. This is partly due to inadequate monitoring of the three interrelated treatment parameters: treatment light, photosensitizer and tissue oxygenation. This thesis presents the development of a system for explicit dosimetry of PDT treatment light and tissue oxygenation using multi-sensor fiber optic probes for spatially resolved parameter measurements. The system uses embedded fluorescent sensors for treatment light quantification. Tissue oxygenation measurement is accomplished using frequency domain techniques with embedded phosphorescent metalloporphyrin compounds as sensors.

Tissue equivalent proportional counters (TEPC) are used for medical and space activities whenever a combination of high and low LET (lineal energy transfer) radiations are present. With the frequency and duration of space activities increasing, exposure to fast heavy ions from galactic cosmic radiation and solar events is a major concern. The optimum detector geometry is spherical; to obtain an isotropic response, but simple spherical detectors have the disadvantage of a non-uniform electric field. In order to achieve a uniform electric field along the detector axis, spherical tissue equivalent proportional counters have been designed with different structures to modify the electric field. Some detectors use a cylindrical coil that is coaxial with the anode, but they are not reliable because of their sensitivity to microphonic noise and insufficient mechanical strength. In this work a new spherical TEPC was developed. The approach used was to divide the cathode in several rings with different thicknesses, and adjust the potential difference between each ring and the anode to produce an electric field that is nearly constant along the length of the anode. A-150 tissue equivalent plastic is used for the detector walls, the insulator material between the cathode rings is low density polyethylene, and the gas inside the detector is propane. The detector, along with the charge sensitive preamplifier, is encased in a stainless steel vacuum chamber. The gas gain was found to be 497.5 at 782 volts and the response to neutrons as a function of angle was constant ±7%. This spherical tissue equivalent proportional counter detector system will improve the accuracy of dosimetry in space, and as a result improve radiation safety for astronauts.

Current brachytherapy treatment planning systems are unable to accurately calculate dose distributions in the vicinity of brachytherapy sources having active lengths much greater than 5 mm. While low dose-rate ¹³⁷Cs sources are dosimetrically characterized using antiquated along-away tables with simple linear-linear interpolation errors in dose calculation exceeding 30% occur due to algorithm inadequacy. The method presented in this thesis permits dosimetric characterization of elongated brachytherapy sources with active lengths 0 < L < 10 cm for implementation on an FDA-approved clinical TPS. Low- and high-energy photon-emitting sources of Pd-103 and Ir-192, respectively, were examined.

Thesis (M.S. in Electrical Engineering)--Naval Postgraduate School, September 2003. / Thesis advisor(s): Todd R. Weatherford, Andrew A. Parker. Includes bibliographical references (p. 39). Also available online.

In photodynamic therapy (PDT), the combination of light, photosensitizer and molecular oxygen generates reactive oxygen species, including singlet oxygen (1O2), which is regarded as the primary cytotoxin and effector with most clinical photosensitizers. PDT has gained some acceptance for the treatment of cancer and other conditions. However, its clinical utility and effectiveness has been limited by variability in treatment response and failure to integrate adequate treatment planning and dosimetry. Direct PDT dosimetry through the detection of ultra-weak near-infrared 1O2 luminescence emission at 1270 nm (SOL) collapses the complexity of PDT into a single parameter, the 1O2 concentration. Prior to the present studies, it was shown that SOL was well correlated with PDT response in vitro and in vivo under controlled experimental conditions. However, SOL detection is technically challenging because of the very low radiative probability of 1O2 (~ 10-8 in biological environments), dynamic background signals and limited sensitivity of suitable photodetectors in this wavelength region. A technologically simpler and less costly PDT dosimetry approach is to use photosensitizer photobleaching to estimate the 1O2 dose. The first objective in this thesis was to characterize the dynamics of SOL measurements, in particular the influence of oxygen depletion, in order to improve the quantification of SOL and its use as an accurate PDT dose metric. Subsequently, direct comparison of SOL and photobleaching-based dosimetry during in vitro PDT treatment with meso-tetra(hydroxyphenyl)chlorin (mTHPC) showed that SOL dosimetry is robust but that photobleaching-based dosimetry can fail under hypoxic conditions. However, the latter can be salvaged through the identification of a previously unreported 613 nm emission from mTHPC that indicates hypoxia. These studies were carried forward into an in vivo dorsal skin-fold window chamber tumor model, which showed promising initial correlation between 1O2 dose and tumor response. This work also identified SOL detection limitations and opportunities for further development. Additionally, SOL measurements were used as a ‘gold standard’ to evaluate novel activatable PDT beacons and a novel “PDT biodosimeter” based on STAT3 cross-linking. Future work includes further tumor dose-response studies, characterization of novel photosensitizing agents, improvement on signal detection and processing, and studies in normal human skin.

In photodynamic therapy (PDT), the combination of light, photosensitizer and molecular oxygen generates reactive oxygen species, including singlet oxygen (1O2), which is regarded as the primary cytotoxin and effector with most clinical photosensitizers. PDT has gained some acceptance for the treatment of cancer and other conditions. However, its clinical utility and effectiveness has been limited by variability in treatment response and failure to integrate adequate treatment planning and dosimetry. Direct PDT dosimetry through the detection of ultra-weak near-infrared 1O2 luminescence emission at 1270 nm (SOL) collapses the complexity of PDT into a single parameter, the 1O2 concentration. Prior to the present studies, it was shown that SOL was well correlated with PDT response in vitro and in vivo under controlled experimental conditions. However, SOL detection is technically challenging because of the very low radiative probability of 1O2 (~ 10-8 in biological environments), dynamic background signals and limited sensitivity of suitable photodetectors in this wavelength region. A technologically simpler and less costly PDT dosimetry approach is to use photosensitizer photobleaching to estimate the 1O2 dose. The first objective in this thesis was to characterize the dynamics of SOL measurements, in particular the influence of oxygen depletion, in order to improve the quantification of SOL and its use as an accurate PDT dose metric. Subsequently, direct comparison of SOL and photobleaching-based dosimetry during in vitro PDT treatment with meso-tetra(hydroxyphenyl)chlorin (mTHPC) showed that SOL dosimetry is robust but that photobleaching-based dosimetry can fail under hypoxic conditions. However, the latter can be salvaged through the identification of a previously unreported 613 nm emission from mTHPC that indicates hypoxia. These studies were carried forward into an in vivo dorsal skin-fold window chamber tumor model, which showed promising initial correlation between 1O2 dose and tumor response. This work also identified SOL detection limitations and opportunities for further development. Additionally, SOL measurements were used as a ‘gold standard’ to evaluate novel activatable PDT beacons and a novel “PDT biodosimeter” based on STAT3 cross-linking. Future work includes further tumor dose-response studies, characterization of novel photosensitizing agents, improvement on signal detection and processing, and studies in normal human skin.

Experimental studies were undertaken to improve the radiation dose response and ease of manufacture of polymer gel dosimeters that use N-isopropyl acrylamide (NIPAM) as the monomer. An alternative carageenan gelling agent was tested in place of gelatin. Although the carageenan did reduce the gelling time for the dosimeter solution, the dose response of the dosimeters was unsatisfactory. An alternative antioxidant system, ascorbic acid and Cu2+, was investigated with the aim of reducing the toxicity of dosimeter materials and providing opportunities for commercial production of prepackaged dosimeter kits. Unfortunately, the new antioxidant was ineffective for the NIPAM-based dosimeters that were studied. Three cosolvents, glycerol, N-propanol and isopropanol, were used to increase the solubility of N,N’-methylene-bisacrylamide (Bis) crosslinker in polymer gel dosimeter recipes that use NIPAM. These cosolvents enabled the manufacture of polymer gel dosimeters with higher levels of dissolved crosslinker than was previously possible. Preliminary results using x-ray computed tomography to read the resulting gels are very promising, due to enhancements in dose sensitivity. Dosimeters with high N,N’-methylene-bisacrylamide content that used isopropanol or glycerol as cosolvents had good optical clarity prior to irradiation, but did not produce reliable optical CT results for non-uniformly-irradiated gels. Further experiments and recipe optimization are required to determine whether gels with cosolvents and high levels of N,N’-methylene bisacrylamide can be used effectively for verifying spatially non-uniform dose distributions using x-ray computed tomography. A mathematical model that includes inhibition of NIPAM-Bis polymerization was developed and the inhibition effects of MEHQ and oxygen in polymer gel dosimeters were simulated. Kinetic parameters were obtained from the literature and were estimated using experimental data obtained by our research group. Good agreement was obtained between model predictions and experimental data with and without oxygen contamination. Simulation results indicate that MEHQ has little influence on the duration of the inhibition period and the rate of polymerization when no oxygen contamination is present, so that removal of MEHQ from dosimeter recipes is not required. Effective oxygen removal is very important to achieve reliable dosimeter results. / Thesis (Master, Chemical Engineering) -- Queen's University, 2008-12-16 15:59:14.034

Energy modulated electron therapy (EMET) is a promising treatment modality that has the fundamental capabilities to enhance the treatment planning and delivery of superficially located targets. Although it offers advantages over x-ray intensity modulated radiation therapy (IMRT), EMET has not been widely implemented to the same level of accuracy, automation, and clinical routine as its x-ray counterpart. This lack of implementation is attributed to the absence of a remotely automated beam shaping system as well as the deficiency in dosimetric accuracy of clinical electron pencil beam algorithms in the presence of beam modifiers and tissue heterogeneities. In this study, we present a novel technique for treatment planning and delivery of EMET. The delivery is achieved using a prototype of an automated "few leaf electron collimator" (FLEC). It consists of four copper leaves driven by stepper motors which are synchronized with the x-ray jaws in order to form a series of collimated rectangular openings or "fieldlets". Based on Monte Carlo studies, the FLEC has been designed to serve as an accessory tool to the current accelerator equipment. The FLEC was constructed and its operation was fully automated and integrated with the accelerator through an in-house assembled control unit. The control unit is a portable computer system accompanied with customized software that delivers EMET plans after acquiring them from the optimization station. EMET plans are produced based on dose volume constraints that employ Monte Carlo pre-generated and patient-specific kernels which are utilized by an in-house developed optimization algorithm. The structure of the optimization software is demonstrated. Using Monte Carlo techniques to calculate dose allows for accurate modeling of the collimation system as well as the patient heterogeneous geometry and take into account their impact on optimization. The Monte Carlo calculations were validated by comparing them against output measurements with an ionization chamber. Comparisons with measurements using nearly energy-independent radiochromic films were performed to confirm the Monte Carlo calculation accuracy for 1-D and 2-D dose distributions. We investigated the clinical significance of EMET on cancer sites that are inherently difficult to plan with IMRT. Several parameters were used to analyze treatment plans where they show that EMET provides significant overall improvements over IMRT.

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