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The distributions of light and tissue oxygenation (St O2 ) within the chest cavity were determined for 15 subjects undergoing macroscopic complete resection followed by intraoperative photodynamic therapy (PDT) as part of a clinical trial for the treatment of malignant pleural mesothelioma (MPM). Over the course of light delivery, detectors at each of eight different sites recorded exposure to variable fluence rate. Nevertheless, the treatment-averaged fluence rate was similar among sites, ranging from a median of 40-61 mW cm-2 during periods of light exposure to a detector. St O2 at each tissue site varied by subject, but posterior mediastinum and posterior sulcus were the most consistently well oxygenated (median St O2 >90%; interquartile ranges ~85-95%). PDT effect on St O2 was characterized as the St O2 ratio (post-PDT St O2 /pre-PDT St O2 ). High St O2 pre-PDT was significantly associated with oxygen depletion (St O2 ratio < 1), although the extent of oxygen depletion was mild (median St O2 ratio of 0.8). Overall, PDT of the thoracic cavity resulted in moderate treatment-averaged fluence rate that was consistent among treated tissue sites, despite instantaneous exposure to high fluence rate. Mild oxygen depletion after PDT was experienced at tissue sites with high pre-PDT St O2 , which may suggest the presence of a treatment effect.

Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcomes. However, current practice when delivering intrapleural PDT uses a point source to deliver light that is monitored by seven isotropic detectors placed within the pleural cavity to assess its uniformity. We have developed a real-time infrared (IR) tracking camera to follow the movement of the light point source and the surface contour of the treatment area. The calculated light fluence rates were matched with isotropic detectors using a two-correction factor method and an empirical model that includes both direct and scattered light components. Our clinical trial demonstrated that we can successfully implement the IR navigation system in 75% (15/20) of the patients. Data were successfully analyzed in 80% (12/15) patients because detector locations were not available for three patients. We conclude that it is feasible to use an IR camera-based system to track the motion of the light source during PDT and demonstrate its use to quantify the uniformity of light distribution, which deviated by a standard deviation of 18% from the prescribed light dose. The navigation system will fail when insufficient percentage of light source positions is obtained (

Background Total skin electron therapy (TSET) utilizes high-energy electrons to treat malignancies on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interactions between the high-energy electron beam and tissue. Methods and materials With a time-gated intensified camera system, the Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real time. Fifteen patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. Each patient was monitored during TSET via in vivo detectors (IVD) in nine locations. For accurate Cherenkov imaging, a comparison between IVD and Cherenkov profiles was conducted using a polyvinyl chloride board to establish the perspective corrections. Results and discussion With proper corrections developed in this study including the perspective and inverse square corrections, the Cherenkov imaging provided two-dimensional maps proportional to dose and projected on patient skin. The results of ratio between chest and umbilicus points were in good agreement with in vivo point dose measurements, with a standard deviation of 2.4% compared to OSLD measurements. Conclusions Cherenkov imaging is a viable tool for validating patient-specific dose distributions during TSET.

PDT efficacy depends on the availability and dynamic interactions of photosensitizer, light, and oxygen. Tissue optical properties influence the delivered light dose and impact PDT outcome. In-vivo measurements of tissue optical properties and photosensitizer concentration enable determination of explicit and implicit dose factors affecting PDT and helps to understand the underlying biophysical mechanism of PDT. In this study, we measure tissue optical properties (absorption μ(a) (λ) and scattering μ(s)’ (λ) coefficients) and PpIX concentration in tissue simulating liquid phantoms with a geometry that resembles anal canal. In-vivo light fluence rate and photosensitizer fluorescence of 405nm excitation light source were acquired using a dual-motor continuous wave transmittance spectroscopy system. We characterized the tissue optical properties correction factor of fluorescence signal using a series of tissue simulating phantoms with known PpIX concentrations and with absorption coefficient between 0.1 – 0.9 cm(−1) and reduced scattering coefficient between 5 – 40 cm(−1). The results demonstrated that our spectroscopy system could determine the distribution of tissue optical properties and PPIX concentration during anal PDT.

Total Skin Electron Therapy (TSET) utilizes high-energy electrons to treat cancers on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interaction between the high-energy electron beam and tissue. Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real-time using a time-gated intensified camera system. Each patient was monitored during TSET by in-vivo detectors (IVD) as well as Scintillators. Patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. A rigorous methodology for converting Cherenkov intensity to surface dose as products of correction factors, including camera vignette correction factor, incident radiation correction factor, and tissue optical properties correction factor. A comprehensive study has been carried out by inspecting various positions on the patients such as vertex, chest, perineum, shins, and foot relative to the umbilicus point (the prescription point).

Photosensitizer fluorescence emission during photodynamic therapy (PDT) can be used to estimate for in vivo photosensitizer concentration. We built a surface contact probe with 405nm excitation light source to obtain Photofrin fluorescence signal during clinical PDT. The probe was equipped with multiple detector fibers that were located at distances between 0.14 to 0.87 cm laterally from the excitation source fiber. In this study, we investigated the probing depth of fluorescence in biological tissue with different source-detector separation using our contact probe setup. We used Monte Carlo method to simulate the 405nm excitation light and 630nm fluorescence probing depth at various source and detector (SD) separations. The results provided insight to the most probable depth of origin of detected fluorescence at each SD separation and help to understand the in vivo depth distribution of clinically measured Photofrin concentration.

Malignant tissues can be effectively treated by Total Skin Electron Therapy (TSET) over the entire body surface using 6 MeV electron beams. During the radiation treatment, Cherenkov photons are emitted from the patient's skin, and can potentially be used for in-vivo imaging of the radiation dose distribution. A Monte Carlo (MC) simulation toolkit TOPAS is used to study the generation and propagation of Cherenkov photons that are generated from the interaction of electron radiation with human tissues, and to understand the relationship between the dose distributions and the Cherenkov photon distributions. Validation of MC simulations with experiments are performed at 100 SSD and 500 SSD, and simulations of a patient phantom in realistic clinical treatment setups have been done. These simulations with TOPAS show that the emitted Cherenkov distributions at phantom surfaces closely follow their corresponding dose distributions.

Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e., incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration.

Reactive oxygen species explicit dosimetry (ROSED) has been recently developed and demonstrated to be able to better correlate with treatment outcome in both preclinical type I and type II PDT. ROSED involves direct measurements of in-vivo light fluence (rate), in-vivo photosensitizer concentration and tissue oxygenation to calculate for reacted ROS concentration ([ROS]rx) generated by PDT processes. In this study, we demonstrated ROSED in ALA-mediated PDT for mice bearing radiation-induced fibrosacorma (RIF) tumor. PDT treatments were performed using single or fractionated illumination to a same total fluence of 140Jcm-2. The effects of light fractionation on the total reacted [ROS]rx and treatment outcomes were evaluated.

Determination of in-vivo tissue optical properties for anal photodynamic therapy (PDT) is challenging due to the light integrating-sphere effect in an enclosed cylindrical cavity. We developed a model for optical properties determination for anal PDT from measurements of light fluence rate inside a cylindrical cavity submerged in tissue-mimicking liquid phantoms. Measurements are performed in a set of phantoms with known optical properties (μa = 0.1-0.9 cm-1) and (μs’ = 6.65-19.95 cm-1) and the primary and scatter light fluence rates are determined. We developed an analytical expression to relate scatter light fluence rate measured in an enclosed cylindrical geometry to the surrounding tissue optical properties in tissue-simulating liquid phantoms. In addition, the accuracy of determining tissue optical properties using the model was evaluated by comparing the recovered optical properties to the known optical properties of a series of independent test phantoms.

Pleural photodynamic therapy (PDT) is performed intraoperatively for the treatment of microscopic disease in patients with malignant pleural mesothelioma. Accurate delivery of light dose is critical to PDT efficiency. As a standard of care, light fluence is delivered to the prescribed fluence using eight isotropic detectors in pre-determined discrete locations inside the pleural cavity that is filled with a dilute Intralipid solution. An optical infrared (IR) navigation system was used to monitor reflective passive markers on a modified and improved treatment delivery wand to track the position of the light source within the treatment cavity during light delivery. This information was used to calculate the light dose, incorporating a constant scattered light dose and using a dual correction method. Calculation methods were extensively compared for eight detector locations and seven patient case studies. The light fluence uniformity was also quantified by representing the unraveled three-dimensional geometry on a two-dimensional plane. Calculated light fluence at the end of treatment delivery was compared to measured values from isotropic detectors. Using a constant scattered dose for all detector locations along with a dual correction method, the difference between calculated and measured values for each detector was within 15%. Primary light dose alone does not fully account for the light delivered inside the cavity. This is useful in determining the light dose delivered to areas of the pleural cavity between detector locations, and can serve to improve treatment delivery with implementation in real-time in the surgical setting. We concluded that the standard deviation of light fluence uniformity for this method of pleural PDT is 10%.

This chapter is intended to help make inroads to the role of Intralipid in photodynamic therapy (PDT). In addition to Intralipid's favorable property as a light scattering agent, we hypothesized that it will be unstable to photosensitized oxidation. To explore this, measurements of total quenching rate constants (kT) of singlet oxygen with Intralipid and its constituents are described. Furthermore, organic phosphines were tested to trap Intralipid peroxides formed in photosensitized oxidation reactions. Our findings indicate that the vulnerability of Intralipid to photooxidation might suggest limits of its use in PDT.

Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (ϕ) effects, which impact the photochemical oxygen consumption rate, are not accounted for. In this preclinical study, reacted reactive oxygen species ([ROS]rx) was investigated as a dosimetric quantity for PDT outcome. The ability of [ROS]rx to predict the cure index (CI) of tumor growth, CI = 1 − k / k ctr, where k and k ctr are the growth rate of tumor under PDT study and the control tumor without PDT, respectively, for benzoporphyrin derivative (BPD)-mediated PDT, was examined. Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated with different in-air fluences (Φ = 22.5 to 166.7 J / cm2) and in-air fluence rates (ϕair = 75 to 250 mW / cm2) with a BPD dose of 1 mg / kg and a drug-light interval (DLI) of 15 min. Treatment was delivered with a collimated laser beam of 1-cm-diameter at 690 nm. Explicit measurements of in-air light fluence rate, tissue oxygen concentration, and BPD concentration were used to calculate for [ROS]rx. Light fluence rate at 3-mm depth (ϕ3 mm), determined based on Monte-Carlo simulations, was used in the calculation of [ROS]rx at the base of tumor. CI was used as an endpoint for three dose metrics: light fluence, PDT dose, and [ROS]rx. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ3 mm. Preliminary studies show that [ROS]rx best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome. The threshold dose for [ROS]rx for vascular BPD-mediated PDT using DLI of 15 min is determined to be 0.26 mM and is about 3.8 times smaller than the corresponding value for conventional BPD-mediated PDT using DLI of 3 h.

Explicit dosimetry of treatment light fluence and implicit dosimetry of photosensitizer photobleaching are commonly used methods to guide dose delivery during clinical PDT. Tissue oxygen, however, is not routinely monitored intra-operatively even though it is one of the three major components of treatment. Quantitative information about in vivo tissue oxygenation during PDT is desirable, because it enables reactive oxygen species explicit dosimetry (ROSED) for prediction of treatment outcome based on PDT-induced changes in tumor oxygen level. Here we demonstrate ROSED in a clinical setting, Photofrin-mediated pleural photodynamic therapy, by utilizing tumor blood flow information measured by diffuse correlation spectroscopy (DCS). A DCS contact probe was sutured to the pleural cavity wall after surgical resection of pleural mesothelioma tumor to monitor tissue blood flow (blood flow index) during intraoperative PDT treatment. Isotropic detectors were used to measure treatment light fluence and photosensitizer concentration. Blood-flow-derived tumor oxygen concentration, estimated by applying a preclinically determined conversion factor of 1.5×10(9) μMs/cm(2) to the blood flow index, was used in the ROSED model to calculate the total reacted reactive oxygen species [ROS]rx. Seven patients and 12 different pleural sites were assessed and large inter- and intra-patient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J/cm(2) was prescribed to all patients.

Background We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (StO2) and blood volume (tHb) were studied for associations with patient outcomes. Methods PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion StO2 and tHb was measured. Results Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but StO2 was higher in patients with CR. In tongue/FOM lesions, baseline StO2 [mean(SE)] was 54(4)% in patients (n = 12) with CR versus 23(8)% in patients (n = 6) with local recurrence/persistence (p = 0.01). Similarly, for intact disease, baseline StO2 was 54(3)% in patients (n = 10) with CR versus 28(8)% in patients (n = 5) without CR (p = 0.03). In patients with intact disease, higher baseline StO2 associated with 24-month local control (p = 0.02). Conclusions Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT.

Purpose The purpose of this study was to evaluate dose prescription and recording compliance to international standard (International Commission on Radiation Units & Measurements [ICRU]-83) in patients treated with intensity modulated radiation therapy (IMRT) among academic institutions. Methods and materials Ten institutions participated in this study to collect IMRT data to evaluate compliance to ICRU-83. Under institutional review board clearance, data from 5094 patients—including treatment site, technique, planner, physician, prescribed dose, target volume, monitor units, planning system, and dose calculation algorithm—were collected anonymously. The dose-volume histogram of each patient, as well as dose points, doses delivered to 100% (D100), 98% (D98), 95% (D95), 50% (D50), and 2% (D2), of sites was collected and sent to a central location for analysis. Homogeneity index (HI) as a measure of the steepness of target and is a measure of the shape of the dose-volume histogram was calculated for every patient and analyzed. Results In general, ICRU recommendations for naming the target, reporting dose prescription, and achieving desired levels of dose to target were relatively poor. The nomenclature for the target in the dose prescription had large variations, having every permutation of name and number contrary to ICRU recommendations. There was statistically significant variability in D95, D50, and HI among institutions, tumor site, and technique with P values Conclusions Nearly 95% of patient treatments deviated from the ICRU-83 recommended D50 prescription dose delivery. This variability is significant (P

Photodynamic therapy (PDT) is an effective non-ionizing treatment modality that is currently being used for various malignant and non-malignant diseases. In type II PDT with photosensitizers such as benzoporphyrin monoacid ring A (BPD), cell death is based on the creation of singlet oxygen ( 1 O 2 ). With a previously proposed empirical five-parameter macroscopic model, the threshold dose of singlet oxygen ([ 1 O 2 ] rx,sh ]) to cause tissue necrosis in tumors treated with PDT was determined along with a range of the magnitude of the relevant photochemical parameters: the photochemical oxygen consumption rate per light fluence rate and photosensitizer concentration ( ξ ), the probability ratio of 1 O 2 to react with ground state photosensitizer compared to a cellular target ( σ ), the ratio of the monomolecular decay rate of the triplet state photosensitizer ( β ), the low photosensitizer concentration correction factor ( δ ), and the macroscopic maximum oxygen supply rate ( g ). Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated interstitially with a linear light source at 690 nm with total energy released per unit length of 22.5–135 J/cm and source power per unit length of 12–150 mW/cm to induce different radii of necrosis. A fitting algorithm was developed to determine the photochemical parameters by minimizing the error function involving the range between the calculated reacted singlet oxygen ([ 1 O 2 ] rx ) at necrosis radius and the [ 1 O 2 ] rx,sh . [ 1 O 2 ] rx was calculated based on explicit dosimetry of the light fluence distribution, the tissue optical properties, and the BPD concentration. The initial ground state oxygen concentration ([ 3 O 2 ] 0 ) was set to be 40 μM in this study. The photochemical parameters were found to be ξ = (55 ± 40) × 10 − 3 cm 2 mW − 1 s − 1 , σ = (1.8 ± 3) × 10 − 5 μM − 1 , and g = 1.7 ± 0.7 μM s − 1 . We have taken the literature values for δ = 33 μM, and β = 11.9 μM. [ 1 O 2 ] rx has shown promise to be a more effective dosimetry quantity for predicting necrosis than either light dose or PDT dose, where the latter is simplistically a temporal integral of the products of the photosensitizer concentration and light fluence rate.

As part of a preclinical trial for the treatment of peritoneal carcinomatosis (PC) with photodynamic therapy (PDT), we have assessed changes in optical properties, tissue oxygenation and drug concentration as a result of benzoporphyrin derivative (BPD)-mediated PDT using diffuse reflectance and fluorescence measurements. PDT can effectively treat superficial disease spread, but treatment efficacy is influenced by physical properties of the treated tissue which can change over the treatment time. In this study, healthy canines were given BPD and irradiated with 690 nm light during a partial bowel resection, and spectroscopic and fluorescence measurements were made using an in-house built spectroscopic probe. Hemoglobin concentration, oxygenation and optical properties were determined to be highly heterogeneous between canines and at different anatomical locations within the same subject, so further development of PDT dosimetry systems will need to address this patient and location-specific dose optimization. Compared to other photosensitizers, we found no apparent BPD photobleaching after PDT.

Uniform delivery of light fluence is an important goal for photodynamic therapy. We present summary results for an infrared (IR) navigation system to deliver light dose uniformly during intracavitory PDT by tracking the movement of the light source and providing real-time feedback on the light fluence rate on the entire cavity surface area. In the current intrapleural PDT protocol, 8 detectors placed in selected locations in the pleural cavity monitor the light doses. To improve the delivery of light dose uniformity, an IR camera system is used to track the motion of the light source as well as the surface contour of the pleural cavity. A MATLAB-based GUI program is developed to display the light dose in real-time during PDT to guide the PDT treatment delivery to improve the uniformity of the light dose. We have developed an improved model for direct light calculation that accounts for the anisotropy of the light from the light sources. A comprehensive analysis of the distribution of light fluence during HPPH and Photofrin PDT is presented in clinical cases and the improvements between the two protocol are discussed.

Determination of in-vivo tissue optical properties for anal photodynamic therapy (PDT) is challenging due to the light integrating-sphere effect in an enclosed cylindrical cavity. We developed a model for optical properties determination for anal PDT from measurements of light fluence rate inside a cylindrical cavity submerged in tissue-mimicking liquid phantoms. Measurements are performed in a set of phantoms with known optical properties (μa = 0.1-0.9 cm-1) and (μs’ = 5.5-16.5 cm-1) and the primary and scatter light fluence rates are determined. We developed a forward empirical model to relate scatter light fluence rate measured in an enclosed cylindrical geometry to the surrounding tissue optical properties in tissue-simulating liquid phantoms.

Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to calculate reactive oxygen species concentration ([ROS](rx)) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Singlet oxygen is the primary cytotoxic species for ROS, which is responsible for cell death in type II PDT, although other type I ROS is included in the parameters used in our model. Using a combination of fluences (50–250 J/cm(2)) and ϕ (50 – 150 mW/cm(2)), tumor regrowth rate, k, was determined for each condition by fitting the tumor volume vs. time to V(0)*exp(k*t). Treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and Photofrin concentration was used to calculate [ROS](rx,cal). ϕ was determined for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Tissue oxygenation is measured using an oxylite oxygen probe to throughout the treatment to calculate the measured [ROS](rx,mea). Cure index, CI = 1-k/k(ctr), for tumor gowth up to 14 days were determined as an endpoint using five dose metrics: light fluence, PDT dose, and [ROS](rx,cal), and [ROS](rx,mea). PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ at a 3 mm tumor depth. Preliminary studies show that [ROS](rx,mea) best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome.

Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence, and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (ϕ) effects are not accounted for, which has a large effect on the oxygen consumption rate. In this preclinical study, reacted reactive oxygen species ([ROS]rx) was investigated as a dosimetric quantity for PDT outcome. We studied the ability of [ROS]rx to predict the cure index (CI) after PDT of murine tumors; CI = 1 - k/kctr, where k and kctr are the growth rate of PDT-treated and control(untreated) tumor, respectively. Mice bearing radiation induced fibrosarcoma (RIF) tumors were treated with BPD-mediated PDT at different in-air fluences (22.5, 40, 45, 50, 70 and 100 J/cm2) and in-air ϕ (75 and 150 mW/cm2) with a BPD dose of 1 mg/kg and a drug-light interval of 15 mins. Treatment was delivered with a collimated laser beam of 1 cm diameter at 690 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and BPD concentration was used to calculate [ 1 O 2 ] rx . ϕ was calculated for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. CI was used as an endpoint for four dose metrics: light fluence, PDT dose, and [ROS]rx. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ at a 3 mm tumor depth. Preliminary studies show that [ROS]rx best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome. The threshold dose for [ROS]rx is determined to be 0.23 mM and is about 4.3 times smaller than the corresponding value for conventional BPD-mediated PDT using DLI of 3 hrs.

We compare previously reported benzoporphyrin derivative (BPD)-mediated photodynamic therapy (PDT) results for reactive singlet oxygen concentration (also called singlet oxygen dose) on mice with simulations using a computational device, Dosie™, that calculates light transport and photokinetics for PDT in near real-time. The two sets of results are consistent and validate the use of the device in PDT treatment planning to predict BPD-mediated PDT outcomes in mice animal studies based on singlet oxygen dose, which showed a much better correlation with the cure index than the conventional light dose.

Total Skin Electron Therapy (TSET) utilizes high-energy electrons to treat cancers on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interaction between the high-energy electron beam and tissue. Cherenkov emission is used to evaluate the dose uniformity on the surface of the patient in real-time. We have utilized a structured light sensor to determine the surface contour of each patient. Each patient was also monitored during TSET via in-vivo detectors (IVD) and/or scintillating discs in nine locations. The Cherenkov image is converted to dose distribution after a two-dimensional perspective geometry correction and the IVD measured dose at umbilicus. Cumulative dose on patient surface is obtained by projecting the two-dimensional dose distribution onto a cylindrical geometry representing the patient anatomic geometry. Patients undergoing TSET in various conditions (whole body and half body) were imaged and analysed, and the cumulative dose based on Cherenkov imaging was evaluated on various patients.

Purpose: Quality assurance (QA) of dose homogeneity in total skin electron therapy (TSET) is challenging since each patient is positioned in six standing poses with two beam angles. Our study tested the feasibility of a unique approach for TSET QA through computational display of the cumulative dose, constructed and synthesized by computer animation methods. Approach: Dose distributions from Cherenkov emission images were projected onto a scanned 3D body model. Topographically mapped surfaces of the patient were recorded in each of six different delivery positions, while a Cherenkov camera acquired images. Computer animation methods allowed a fitted 3D human body model of the patient to be created with deformation of the limbs and torso to each position. A two-dimensional skin map was extracted from the 3D model of the full surface of the patient. This allowed the dose mapping to be additively accumulated independent of body position, with the total dose summed in a 2D map and reinterpreted on the 3D body display. Results: For the body model, the mean Hausdorff error distance was below 2 cm, setting the spatial accuracy limit. The dose distribution over the patient’s 3D model generally matched the Cherenkov/dose images. The dose distribution mapping was estimated to be near 1.5 cm accuracy based upon a phantom study. The body model must most closely match at the edges of the mesh to ensure that high dose gradients are not projected onto the wrong location. Otherwise 2 to 3 cm level errors in positioning in the mesh do not appear to cause larger than 5% dose errors. The cumulative dose images showed regions of overlap laterally and regions of low intensity in the posterior arms. Conclusions: The proposed modeling and animation can be used to visualize and analyze the accumulated dose in TSET via display of the summed dose/Cherenkov images on a single body surface.

Guest Editors introduce the Special Section on Photodynamic Therapy for the Journal of Biomedical Optics, Volume 25, Issue 6.

Photodynamic therapy (PDT) that employs the photochemical interaction of light, photosensitizer and oxygen is an established modality for the treatment of cancer. However, dosimetry for PDT is becoming increasingly complex due to the heterogeneous photosensitizer uptake by the tumor, and complicated relationship between the tissue oxygenation ([(3)O(2)]), interstitial light distribution, photosensitizer photobleaching and PDT effect. As a result, experts argue that the failure to realize PDT’s true potential is, at least partly due to the complexity of the dosimetry problem. In this study, we examine the efficacy of singlet oxygen explicit dosimetry (SOED) based on the measurements of the interstitial light fluence rate distribution, changes of [(3)O(2)] and photosensitizer concentration during Photofrin-mediated PDT to predict long-term control rates of radiation-induced fibrosarcoma tumors. We further show how variation in tissue [(3)O(2)] between animals induces variation in the treatment response for the same PDT protocol. PDT was performed with 5 mg kg(−1) Photofrin (a drug-light interval of 24 h), in-air fluence rates (ϕ(air)) of 50 and 75 mW cm(−2) and in-air fluences from 225 to 540 J cm(−2). The tumor regrowth was tracked for 90 d after the treatment and Kaplan–Meier analyses for local control rate were performed based on a tumor volume ⩽100 mm(3) for the two dosimetry quantities of PDT dose and SOED. Based on the results, SOED allowed for reduced subject variation and improved treatment evaluation as compared to the PDT dose.

PDT efficacy depends on the concentration of photosensitizer, oxygen, and light delivery in patient tissues. In this study, we measure the in-vivo distribution of important dosimetric parameters, namely the tissue optical properties (absorption μ a (λ) and scattering μs ’ (λ) coefficients), photofrin concentration (cphotofrin), blood oxygen saturation (%S t O 2 ), and total hemoglobin concentration (THC), before and after PDT. We characterize the inter- and intra-patient heterogeneity of these quantities and explore how these properties change as a result of PDT treatment. The result suggests the need for real-time dosimetry during PDT to optimize the treatment condition depending on the optical and physiological properties.

Type I photodynamic therapy (PDT) is based on the use of photochemical reactions mediated through an interaction between a tumor-selective photosensitizer, photoexcitation with a specific wavelength of light, and production of reactive oxygen species (ROS). The goal of this study is to develop a model to calculate reactive oxygen species concentration ([ROS]rx) after Tookad®-mediated vascular PDT. Mice with radiation-induced fibrosarcoma (RIF) tumors were treated with different light fluence and fluence rate conditions. Explicit measurements of photosensitizer drug concentration were made via diffuse reflective absorption spectrum using a contact probe before and after PDT. Blood flow and tissue oxygen concentration over time were measured during PDT as a mean to validate the photochemical parameters for the ROSED calculation. Cure index was computed from the rate of tumor regrowth after treatment and was compared against three calculated dose metrics: total light fluence, PDT dose, reacted [ROS]rx. The tumor growth study demonstrates that [ROS]rx serves as a better dosimetric quantity for predicting treatment outcome, as a clinically relevant tumor growth endpoint.

We demonstrate a noninvasive system for real-time monitoring of tumor blood flow and automatic adjustment of treatment light fluence-rate to conserve tumor perfusion during PDT. Improved efficacy was observed using blood-flow informed light delivery.

Photosensitizer fluorescence excited by photodynamic therapy (PDT) treatment light can be used to monitor the in vivo concentration of the photosensitizer and its photobleaching. The temporal integral of the product of in vivo photosensitizer concentration and light fluence is called PDT dose, which is an important dosimetry quantity for PDT. However, the detected photosensitizer fluorescence may be distorted by variations in the absorption and scattering of both excitation and fluorescence light in tissue. Therefore, correction of the measured fluorescence for distortion due to variable optical properties is required for absolute quantification of photosensitizer concentration. In this study, we have developed a four-channel PDT dose dosimetry system to simultaneously acquire light dosimetry and photosensitizer fluorescence data. We measured PDT dose at four sites in the pleural cavity during pleural PDT. We have determined an empirical optical property correction function using Monte Carlo simulations of fluorescence for a range of physiologically relevant tissue optical properties. Parameters of the optical property correction function for Photofrin fluorescence were determined experimentally using tissue-simulating phantoms. In vivo measurements of photosensitizer fluorescence showed negligible photobleaching of Photofrin during the PDT treatment, but large intra- and inter-patient heterogeneities of in vivo Photofrin concentration are observed. PDT doses delivered to 22 sites in the pleural cavity of 8 patients were different by 2.9 times intra-patient and 8.3 times inter-patient.

Background With radiotherapy having entered the era of image guidance, or image-guided radiation therapy (IGRT), imaging procedures are routinely performed for patient positioning and target localization. The imaging dose delivered may result in excessive dose to sensitive organs and potentially increase the chance of secondary cancers and, therefore, needs to be managed. Aims This task group was charged with: a) providing an overview on imaging dose, including megavoltage electronic portal imaging (MV EPI), kilovoltage digital radiography (kV DR), Tomotherapy MV-CT, megavoltage cone-beam CT (MV-CBCT) and kilovoltage cone-beam CT (kV-CBCT), and b) providing general guidelines for commissioning dose calculation methods and managing imaging dose to patients. Materials & methods We briefly review the dose to radiotherapy (RT) patients resulting from different image guidance procedures and list typical organ doses resulting from MV and kV image acquisition procedures. Results We provide recommendations for managing the imaging dose, including different methods for its calculation, and techniques for reducing it. The recommended threshold beyond which imaging dose should be considered in the treatment planning process is 5% of the therapeutic target dose. Discussion Although the imaging dose resulting from current kV acquisition procedures is generally below this threshold, the ALARA principle should always be applied in practice. Medical physicists should make radiation oncologists aware of the imaging doses delivered to patients under their care. Conclusion Balancing ALARA with the requirement for effective target localization requires that imaging dose be managed based on the consideration of weighing risks and benefits to the patient.

Uniform delivery of light fluence is an important goal for photodynamic therapy. We present summary results for an infrared (IR) navigation system to deliver light dose uniformly during intracavitory PDT by tracking the movement of the light source and providing real-time feedback on the light fluence rate on the entire cavity surface area. In the current intrapleural PDT protocol, 8 detectors placed in selected locations in the pleural cavity monitor the light doses. To improve the delivery of light dose uniformity, an IR camera system is used to track the motion of the light source as well as the surface contour of the pleural cavity. A MATLAB-based GUI program is developed to display the light dose in real-time during PDT to guide the PDT treatment delivery to improve the uniformity of the light dose. A dualcorrection algorithm is used to improve the agreement between calculations and in-situ measurements. A comprehensive analysis of the distribution of light fluence during PDT is presented in both phantom conditions and in clinical cases.

Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to evaluate using calculated reacted singlet oxygen concentration ([O21]rx) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma tumors, as singlet oxygen is the primary cytotoxic species responsible for cell death in type II PDT. Using a combination of fluences (50, 135, 200, and 250 J/cm2) and ϕ (50, 75, and 150 mW/cm2), tumor regrowth rate, k, was determined for each condition. A tumor cure index, CI=1−k/kcontrol, was calculated based on the k between PDT-treated groups and that of the control, kcontrol. The measured Photofrin concentration and light dose for each mouse were used to calculate PDT dose and [O21]rx, while mean optical properties (μa=0.9 cm−1, μs′=8.4 cm−1) were used to calculate ϕ for all mice. CI was correlated to the fluence, PDT dose, and [O21]rx with R2=0.35, 0.79, and 0.93, respectively. These results suggest that [O21]rx serves as a better dosimetric quantity for predicting PDT outcome.

This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [1 O2 ]rx , to predict local control rate (LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma (RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm-2 ) and in-air fluence rates (50-150 mW cm-2 ) at Photofrin dosages of 5 and 15 mg kg-1 and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [1 O2 ]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [1 O2 ]rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [1 O2 ]rx ≥ 1.1 mm or PDT dose ≥1200 μm J cm-2 but cannot be predicted with fluence alone. LCR increases with increasing [1 O2 ]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [1 O2 ]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR.

Intrapleural photodynamic therapy (PDT) has been used in combination with lung sparing surgery to treat patients with malignant pleural mesothelioma. The light, photosensitizers and tissue oxygen are the three most important factors required by type II PDT to produce singlet oxygen, 1O2, which is the main photocytotoxic agent that damages the tumor vasculature and stimulates the body’s anti-tumor immune response. Although light fluence rate and photosensitizer concentrations are routinely monitored during clinical PDT, there is so far a lack of a Food and Drug Administration (FDA)-approved non-invasive technique that can be employed clinically to monitor tissue oxygen in vivo. In this paper, we demonstrated that blood flow correlates well with tissue oxygen concentration during PDT and can be used in place of [3O2] to calculate reacted singlet oxygen concentration [1O2]rx using the macroscopic singlet oxygen model. Diffuse correlation spectroscopy (DCS) was used to monitor the change in tissue blood flow non-invasively during pleural PDT. A contact probe with three source and detectors separations, 0.4, 0.7 and 1.0-cm, was sutured to the pleural cavity wall of the patients after surgical resection of the pleural mesothelioma tumor to monitor the tissue blood flow during intraoperative PDT treatment. The changes of blood flow during PDT of 2 patients are found to be in good correlation with the treatment light fluence rate recorded by the isotropic detector placed adjacent to the DCS probe. [1O2]rx calculated based on light fluence, mean photosensitizer concentration, and relative blood flow was found to be 32% higher in patient #4 (0.50mM) than that for patient #3 (0.38mM).

Photodynamic therapy (PDT) involves interactions between the three main components of light fluence, photosensitizer concentration, and oxygenation. Currently, singlet oxygen explicit dosimetry (SOED) has focused on the first two of these components. The macroscopic model to calculate reacted singlet oxygen has previously involved a fixed initial ground state oxygen concentration. A phosphorescence-based oxygen probe was used to measure ground state oxygen concentration throughout treatments for mice bearing radioactively induced fibroscarcoma tumors. Photofrin-, BPD-, and HPPH-mediated PDT was performed on mice. Model-calculated oxygen and measured oxygen was compared to evaluate the macroscopic model as well as the photochemical parameters involved. Oxygen measurements at various depths were compared to calculated values. Furthermore, we explored the use of noninvasive diffuse correlation spectroscopy (DCS) to measure tumor blood flow changes in response to PDT to improve the model calculation of reacted singlet oxygen. Mice were monitored after treatment to see the effect of oxygenation on long-term recurrence-free survival as well as the efficacy of using reacted singlet oxygen as a predictive measure of outcome. Measurement of oxygenation during treatment helps to improve SOED as well as confirm the photochemical parameters involved in the macroscopic model. Use of DCS in predicting oxygenation changes was also investigated.

Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence, photosensitizer photobleaching rate, and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (Φ) effects are not accounted for, which has a large effect on the oxygen consumption rate. In this preclinical study, reacted singlet oxygen [1O2]rx was investigated as a dosimetric quantity for PDT outcome. The ability of [1O2]rx to predict the long-term local tumor control rate (LCR) for BPD-mediated PDT was examined. Mice bearing radioactivelyinduced fibrosarcoma (RIF) tumors were treated with different in-air fluences (250, 300, and 350 J/cm2) and in-air ϕ (75, 100, and150 mW/cm2) with a BPD dose of 1 mg/kg and a drug-light interval of 3 hours. Treatment was delivered with a collimated laser beam of 1 cm diameter at 690 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and BPD concentration was used to calculate [1O2]rx. Φ was calculated for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Kaplan-Meier analyses for LCR were done for an endpoint of tumor volume ≤ 100 mm3 using four dose metrics: light fluence, photosensitizer photobleaching rate, PDT dose, and [1O2]rx. PDT dose was defined as the product of the timeintegral of photosensitizer concentration and Φ at a 3 mm tumor depth. Preliminary studies show that [1O2]rx better correlates with LCR and is an effective dosimetric quantity that can predict treatment outcome.

This preclinical study examines four dosimetric quantities (light fluence, photosensitizer photobleaching ratio, PDT dose, and reacted singlet oxygen ([1O2]rx)) to predict local control rate (LCR) for 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated photodynamic therapy (PDT). Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated with different in-air fluences (135, 250 and 350 J/cm2) and in-air fluence rates (50, 75 and 150 mW/cm2) at 0.25 mg/kg HPPH and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 665 nm wavelength. A macroscopic model was used to calculate ([1O2]rx)) based on in vivo explicit dosimetry of the initial tissue oxygenation, photosensitizer concentration, and tissue optical properties. PDT dose was defined as a temporal integral of drug concentration and fluence rate (φ) at a 3 mm tumor depth. Light fluence rate was calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. The tumor volume of each mouse was tracked for 30 days after PDT and Kaplan-Meier analyses for LCR were performed based on a tumor volume ≤100 mm3, for four dose metrics: fluence, HPPH photobleaching rate, PDT dose, and ([1O2]rx)). The results of this study showed that ([1O2]rx)) is the best dosimetric quantity that can predict tumor response and correlate with LCR.

We have developed a four-channel PDT dose dosimetry system to simultaneously acquire light dosimetry and sensitizer fluorescence data from four sites in the thoracic cavity during pleural photodynamic therapy (PDT). Photosensitizer fluorescence emitted during PDT is of interest for the monitoring of local concentration of the photosensitizer and its photobleaching. However, the variation in tissue optical properties will cause the photosensitizer fluorescence to alter. Optical properties correction to the measured fluorescence is required for absolute quantification of photosensitizer concentration. In this study, we determine an empirical optical properties correction function using Monte Carlo (MC) simulations of fluorescence for a range of physiologically relevant tissue optical properties. Optical properties correction factors for Photofrin fluorescence were determined experimentally using the same empirical function to recover the Photofrin concentration from measured fluorescence during PDT. The results showed no photobleaching of Photofrin during the course of PDT. PDT doses delivered to multiple sites in the thoracic cavity of 4 patients were presented and showed that PDT dose can be different by 4.4 times intra-patients and 9.1 times inter-patients.

Although photodynamic therapy (PDT) is an established modality for the treatment of cancer, current dosimetric quantities do not account for the variations in PDT oxygen consumption for different fluence rates (φ). In this study we examine the efficacy of reacted singlet oxygen concentration ([1O2]rx) to predict long-term local control rate (LCR) for Photofrin-mediated PDT. Radiation-induced fibrosarcoma (RIF) tumors in the right shoulders of female C3H mice are treated with different in-air fluences of 225-540 J/cm2 and in-air fluence rate (φair) of 50 and 75 mW/cm2 at 5 mg/kg Photofrin and a drug-light interval of 24 hours using a 1 cm diameter collimated laser beam at 630 nm wavelength. [1O2]rx is calculated by using a macroscopic model based on explicit dosimetry of Photofrin concentration, tissue optical properties, tissue oxygenation and blood flow changes during PDT. The tumor volume of each mouse is tracked for 90 days after PDT and Kaplan-Meier analyses for LCR are performed based on a tumor volume ≤100 mm3, for the four dose metrics light fluence, photosensitizer photobleaching rate, PDT dose and [1O2]rx. PDT dose is defined as a temporal integral of photosensitizer concentration and Φ at a 3 mm tumor depth. φ is calculated throughout the treatment volume based on Monte-Carlo simulation and measured tissue optical properties. Our preliminary studies show that [1O2]rx is the best dosimetric quantity that can predict tumor response and correlate with LCR. Moreover, [1O2]rx calculated using the blood flow changes was in agreement with [1O2]rx calculated based on the actual tissue oxygenation.

Photosensitizer photochemical parameters are crucial data in accurate dosimetry for photodynamic therapy (PDT) based on photochemical modeling. Progress has been made in the last few decades in determining the photochemical properties of commonly used photosensitizers (PS), but mostly in solution or in vitro. Recent developments allow for the estimation of some of these photochemical parameters in vivo. This review will cover the currently available in vivo photochemical properties of photosensitizers as well as the techniques for measuring those parameters. Furthermore, photochemical parameters that are independent of environmental factors or are universal for different photosensitizers will be examined. Most photosensitizers discussed in this review are of the type II (singlet oxygen) photooxidation category, although type I photosensitizers that involve other reactive oxygen species (ROS) will be discussed as well. The compilation of these parameters will be essential for ROS modeling of PDT.

Photodynamic therapy (PDT) is known as a non-invasive treatment modality that is based on photochemical reactions between oxygen, photosensitizer, and a special wavelength of light. However, a dosimetric predictor for PDT outcome is still elusive because current dosimetric quantities do not account for the differences in the PDT oxygen consumption rate for different fluence rates. In this study, we evaluate several dose metrics, total fluence, photobleaching ratio, PDT dose, and mean reacted singlet oxygen (mean [1 O2 ]rx ) for predicting the PDT outcome and a clinically relevant tumor re-growth endpoint. For this reason, radiation-induced fibrosarcoma (RIF) mice tumors are treated with 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) and different in-air fluences (30 J/cm2 , 50 J/cm2 , 135 J/cm2 , 250 J/cm2 , and 350 J/cm2 ) and in-air fluence rates (20, 50, 75, 150 mW/cm2 ). Explicit measurements of HPPH and oxygen concentration as well as tissue optical properties are performed pre- and post-treatment. Then, this information is incorporated into a macroscopic model to calculate the photobleaching, PDT dose, and mean [1 O2 ]rx . Changes in tumor volume are tracked following the treatment and compared with the dose metrics. The correlation demonstrates that mean [1 O2 ]rx serves as a better dosimetric quantity for predicting treatment outcome and a clinically relevant tumor re-growth endpoint.

As a nonionizing radiation treatment, photodynamic therapy (PDT) has been used effectively for the treatment of various easily accessible lesions, such as head and neck cancers, esophageal cancers, microinvasive lung cancer, and skin lesions such as premalignant actinic keratosis.1–4 PDT requires the administration of a photosensitizer that localizes in tumor tissue and is excited by the appropriate treatment wavelength of light. With the absorption of light, the photosensizer transitions from its ground state to a short-lived excited singlet state. The singlet state photosensitizer transitions to a longer-lived electronically excited triplet state via intersystem crossing. In typical type II PDT, which is the focus of this study, the triplet state transfers energy to molecular ground state oxygen (O23) that is present in the treatment environment to produce singlet-state oxygen (O21). The production of O21 and reactions with the surrounding biological molecules are thought to be the major cause of cytotoxicity.5 Due to the high reactivity and short lifetime of O21, only cells that are proximal to the area of O21 production are directly affected by PDT.6 For that reason, PDT causes significantly less harm to healthy tissue than chemotherapy or radiation.6,7 A well-defined dosimetric metric for PDT that is able to predict clinical outcomes that can also be implemented in a clinical setting would benefit the advance of the PDT field. Benzoporphyrin derivative monoacid ring A (BPD, trademark Visudyne®) is a commonly used photosensitizer that was approved by the US Food and Drug Administration in 2000 for the treatment of wet age-related macular degeneration.8 Utilizing a macroscopic model, reacted singlet oxygen ([O21]rx) can be calculated to evaluate its effectiveness as a dosimetric predictor for BPD-mediated PDT outcome. In addition, several other dose metrics were evaluated in this study, including total light fluence, photobleaching ratio, and PDT dose, to predict the PDT outcome. Radiation-induced fibrosarcoma (RIF) tumors on mice were treated with BPD-PDT and a range of in-air fluences (30 to 350 J/cm2) and in-air fluence rates (50 to 150 mW/cm2). For each PDT treatment group, explicit measurements of BPD concentration in tumor and tissue optical properties were performed pre- and posttreatment. For a subset of mice, real-time in-vivo measurement of BPD concentration and tissue oxygenation level ([O23]) throughout PDT were taken to optimize the photosensitizer-specific PDT photochemical parameters (ξ, σ, and g), reduce their uncertainty from a previous study, and calculate [O21]rx. These photochemical parameters were used to calculate [O21]rx for each PDT treatment group. Other dose metrics, such as photobleaching ratio and PDT dose, were determined either directly using explicit measurements pre- and post-PDT or calculated using the time dependence of BPD concentration based on the macroscopic model and the definition of PDT dose. This study, to our knowledge, is the first to investigate the threshold value of [O21]rx and the relationship between various dose metrics (fluence, PDT dose, and [O21]rx) and the cure index (CI) at 14 days in an in-vivo mouse model for BPD-mediated PDT. The results of our study with additional real-time measurements of BPD concentration and [O23] provide reduced uncertainties for the photochemical parameters determined for BPD-mediated PDT, as well as a validation that our macroscopic model can accurately predict the oxygen consumption for BPD-mediated PDT, making it feasible to determine [O21]rx without oxygen measurements.

Accurate photodynamic therapy (PDT) dosimetry is critical for the use of PDT in the treatment of malignant and nonmalignant localized diseases. A singlet oxygen explicit dosimetry (SOED) model has been developed for in vivo purposes. It involves the measurement of the key components in PDT—light fluence (rate), photosensitizer concentration, and ground-state oxygen concentration ([3O2])—to calculate the amount of reacted singlet oxygen ([1O2]rx), the main cytotoxic component in type II PDT. Experiments were performed in phantoms with the photosensitizer Photofrin and in solution using phosphorescence-based singlet oxygen luminescence dosimetry (SOLD) to validate the SOED model. Oxygen concentration and photosensitizer photobleaching versus time were measured during PDT, along with direct SOLD measurements of singlet oxygen and triplet state lifetime (τΔ and τt), for various photosensitizer concentrations to determine necessary photophysical parameters. SOLD-determined cumulative [1O2]rx was compared to SOED-calculated [1O2]rx for various photosensitizer concentrations to show a clear correlation between the two methods. This illustrates that explicit dosimetry can be used when phosphorescence-based dosimetry is not feasible. Using SOED modeling, we have also shown evidence that SOLD-measured [1O2]rx using a 523 nm pulsed laser can be used to correlate to singlet oxygen generated by a 630 nm laser during a clinical malignant pleural mesothelioma (MPM) PDT protocol by using a conversion formula.

When the pleural cavity is opened during the surgery portion of pleural photodynamic therapy (PDT) of malignant mesothelioma, the pleural volume will deform. This impacts the delivered dose when using highly conformal treatment techniques. To track the anatomical changes and contour the lung and chest cavity, an infrared camera–based navigation system (NDI) is used during PDT. In the same patient, a series of computed tomography (CT) scans of the lungs are also acquired before the surgery. The reconstructed three-dimensional contours from both NDI and CTs are imported into COMSOL Multiphysics software, where a finite element-based (FEM) deformable image registration is obtained. The CT contour is registered to the corresponding NDI contour by overlapping the center of masses and aligning their orientations. The NDI contour is considered as the reference contour, and the CT contour is used as the target one, which will be deformed. Deformed Geometry model is applied in COMSOL to obtain a deformed target contour. The distortion of the volume at X, Y and Z is mapped to illustrate the transformation of the target contour. The initial assessment shows that FEM-based image deformable registration can fuse images acquired by different modalities. It provides insights into the deformation of anatomical structures along X, Y and Z-axes. The deformed contour has good matches to the reference contour after the dynamic matching process. The resulting three-dimensional deformation map can be used to obtain the locations of other critical anatomic structures, e.g., heart, during surgery.

The macroscopic singlet oxygen model has been used for singlet oxygen explicit dosimetry in photodynamic therapy (PDT). The photophysical parameters for commonly used sensitizers, HPPH and BPD, have been investigated in pre-clinical studies using mouse models. So far, studies have involved optimizing fitting algorithms to obtain the some of the photophysical parameters (ξ, σ, g) and the threshold singlet oxygen dose ([1O2]rx,sh), while other parameters such as the low concentration correction, δ, has been kept as a constant. In this study, using photobleaching measurements of mice in vivo, the value of δ was also optimized and fit to better describe experimental data. Furthermore, the value of the specific photobleaching ratio (σ) was also fine-tuned using the photobleaching results. Based on literature values of δ, σ for photosensitizers can be uniquely determined using the additional photobleaching measurements. This routine will further improve the macroscopic model of singlet oxygen production for use in explicit dosimetry.

Type II photodynamic therapy (PDT) is used for cancer treatment based on the combined action of a photosensitizer, a special wavelength of light, oxygen (3O2) and generation of singlet oxygen (1O2). Intra-patient and inter-patient variability of oxygen concentration ([3O2]) before and after the treatment as well as photosensitizer concentration and hemodynamic parameters such as blood flow during PDT has been reported. Simulation of these variations is valuable, as it would be a means for the rapid assessment of treatment effect. A mathematical model has been previously developed to incorporate the diffusion equation for light transport in tissue and the macroscopic kinetic equations for simulation of [3O2], photosensitizers in ground and triplet states and concentration of the reacted singlet oxygen ([1O₂]rx) during PDT. In this study, the finite-element based calculation of the macroscopic kinetic equations is done for 2-(1- Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH)-mediated PDT by incorporating the information of the photosensitizer photochemical parameters as well as the tissue optical properties, photosensitizer concentration, initial oxygen concentration ([3O2]0), blood flow changes and Φ that have been measured in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Then, [1O2]rx calculated by using the measured [3O2] during the PDT is compared with [1O2]rx calculated based on the simulated [3O₂]; both calculations showed a reasonably good agreement. Moreover, the impacts of the blood flow changes and [3O2]0 on [1O2]rx have been investigated, which showed no pronounced effect of the blood flow changes on the long-term 1O2 generation. When [3O2]0 becomes limiting, small changes in [3O₂] have large effects on [1O2]rx.

An explicit dosimetry model has been developed to calculate the apparent reacted 1O2 concentration ([1O2]rx) in an in-vivo model. In the model, a macroscopic quantity, g, is introduced to account for oxygen perfusion to the medium during PDT. In this study, the SOED model is extended for PDT treatment in phantom conditions where vasculature is not present; the oxygen perfusion is achieved through the air-phantom interface instead. The solution of the SOED model is obtained by solving the coupled photochemical rate equations incorporating oxygen perfusion through the air-liquid interface. Experiments were performed for two photosensitizers (PS), Rose Bengal (RB) and Photofrin, in solution, using SOED and SOLD measurements to determine both the instantaneous [1O2] as well as cumulative [1O2]rx concentrations, where [1O2=(1/τ▵)•∫[1O2]dt. The PS concentrations varied between 10 and 100 mM for RB and ~200 mM for Photofrin. The resulting magnitudes of [1O2] were compared between SOED and SOLD. © (2016) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

It is well known in photodynamic therapy (PDT) that there is a large variability between PDT light dose and therapeutic outcomes. An explicit dosimetry model using apparent reacted 1 O 2 concentration [ 1 O 2 ] rx has been developed as a PDT dosimetric quantity to improve the accuracy of the predicted ability of therapeutic efficacy. In this study, this explicit macroscopic singlet oxygen model was adopted to establish the correlation between calculated reacted [ 1 O 2 ] rx and the tumor growth using Photofrin-mediated PDT in a mouse tumor model. Mice with radiation-induced fibrosarcoma (RIF) tumors were injected with Photofrin at a dose of 5 mg/kg. PDT was performed 24h later with different fluence rates (50, 75 and 150 mW/cm 2 ) and different fluences (50 and 135 J/cm2) using a collimated light applicator coupled to a 630nm laser. The tumor volume was monitored daily after PDT and correlated with the total light fluence and [ 1 O 2 ] rx . Photophysical parameters as well as the singlet oxygen threshold dose for this sensitizer and the RIF tumor model were determined previously. The result showed that tumor growth rate varied greatly with light fluence for different fluence rates while [ 1 O 2 ] rx had a good correlation with the PDT-induced tumor growth rate. This preliminary study indicated that [ 1 O 2 ] rx could serve as a better dosimetric predictor for predicting PDT outcome than PDT light dose.