Light Fluence Dosimetry in Lung-simulating Cavities.

Uniform light fluence distribution for patients undergoing photodynamic therapy (PDT) is critical to ensure predictable PDT outcome. However, common practice uses a point source to deliver light to the pleural cavity. To improve the uniformity of light fluence rate distribution, we have developed a treatment planning system using an infrared camera to track the movement of the point source. This study examines the light fluence (rate) delivered to chest phantom to simulate a patient undergoing pleural PDT. Fluence rate (mW/cm2) and cumulative fluence (J/cm2) was monitored at 7 different sites during the entire light treatment delivery. Isotropic detectors were used for in-vivo light dosimetry. Light fluence rate in the pleural cavity is also calculated using the diffusion approximation with a finite-element model. We have established a correlation between the light fluence rate distribution and the light fluence rate measured on the selected points based on a spherical cavity model. Integrating sphere theory is used to aid the calculation of light fluence rate on the surface of the sphere as well as inside tissue assuming uniform optical properties. The resulting treatment planning tool can be valuable as a clinical guideline for future pleural PDT treatment.

Multispectral singlet oxygen luminescent dosimetry (MSOLD) for Photofrin-mediated PDT

We have developed a method to quickly determine tissue optical properties (absorption coefficient μa and transport scattering coefficient μ′s) by measuring the ratio of light fluence rate to source power along a linear channel at a fixed distance (5 mm) from an isotropic point source. Diffuse light is collected by an isotropic detector whose position is determined by a computer-controlled step motor, with a positioning accuracy of better than 0.1 mm. The system automatically records and plots the light fluence rate per unit source power as a function of position. The result is fitted with a diffusion equation to determine μa and μ′s. We use an integrating sphere to calibrate each source–detector pair, thus reducing uncertainty of individual calibrations. To test the ability of this algorithm to accurately recover the optical properties of the tissue, we made measurements in tissue simulating phantoms consisting of Liposyn at concentrations of 0.23, 0.53 and 1.14% (μ′s = 1.7–9.1 cm−1) in the presence of Higgins black India ink at concentrations of 0.002, 0.012 and 0.023% (μa = 0.1–1 cm−1). For comparison, the optical properties of each phantom are determined independently using broad-beam illumination. We find that μa and μ′s can be determined by this method with a standard (maximum) deviation of 8% (15%) and 18% (32%) for μa and μ′s, respectively. The current method is effective for samples whose optical properties satisfy the requirement of the diffusion approximation. The error caused by the air cavity introduced by the catheter is small, except when μa is large (μa > 1 cm−1). We presented in vivo data measured in human prostate using this method.

Purpose: To develop a method to quickly determine tissue optical properties (absorption coefficient μa and transport scattering coefficient μs') in a semi-infinite medium. Method and material: Optical properties where determined by measuring the ratio of light fluence rate to source power along a linear channel at a fixed distance (4 mm) from an isotropic point source. The light detection system consists of two parallel light transmitting catheters placed 4mm apart. Diffuse light, from a 2mm cylindrical diffusing tip, is collected by an isotropic detector with a 0.5mm scattering bulb whose position is determined by a computer controlled step motor, with a positioning accuracy of better than 0.1 mm. The system automatically records and plots the light fluence rate per unit source power as a function of position. The result is fitted with a diffusion equation to extrapolate μa and μs'. Measurements where made in liquid tissue simulating phantoms, with known reduced scattering coefficient (μs') and absorption coefficient (μa). A theory based on light source on semi-infinite medium has been developed to interpret the measured data. To test the ability of this algorithm to accurately recover the optical properties of the tissue, we made measurements in tissue simulating phantoms consisting of Liposyn concentration of 0.53% (μs' = 3.68cm−1) in the presence of Higgins black India ink at concentrations of 0.002, 0.012 and 0.023% (μa = 0.1 – 1 cm−1). For comparison, the optical properties of the phantom were determined independently using broad-beam illumination. Results: We find that μa and μs' can be determined by this method with a standard (maximum) deviation of 24% (27%) and 29% (42%) for μa and μs', respectively. Conclusion: We developed a model for quick and accurate determination of tissue optical properties in semi-infinite medium, which is theoretically suitable for determination of optical properties for esophagus PDT.

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).

The optical absorption, scattering and anisotropy coefficients of piglet bladder, with and without Photofrin, and of diseased human bladder were determined in vitro with a double integrating sphere set-up in the wavelength range 450-800 nm. Monte Carlo simulations were performed in a spherical geometry, representing the bladder, using the optical properties at 532 nm and 630 nm determined in vitro. The calculated fluence rates support the fluence rates that were measured at the bladder wall of a piglet during an in vivo whole bladder wall (WBW) irradiation at 532 nm and 630 nm. Fluence rates calculated and measured in vivo at 630 nm are in agreement with those measured previously in clinical photodynamic therapy (PDT) at 630 nm. WBW-PDT With red light (630 nm) will be technically more advantageous than with green light (532 nm) because of a stronger integrating sphere effect, which reduces the variations of the fluence rate at the bladder wall when the isotropic light source is moved away from the centre of the bladder. Since the optical properties show considerable variations from bladder to bladder, and since as a result the light fluence rate at the bladder wall can vary by a factor of 3 to 4 for the same non-scattered light fluence rate, we conclude that in situ light dosimetry during clinical WBW-PDT is a necessity.

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 (<30%) during PDT.

We developed a simulation method for modeling the light fluence delivery in intracavity Photodynamic Therapy (icav-PDT) for pleural lung cancer using a moving light source. Due to the large surface area of the pleural lung cavity, the light source needs to be moved to deliver a uniform dose around the entire cavity. While multiple fixed detectors are used for dosimetry at a few locations, an accurate simulation of light fluence and fluence rate is still needed for the rest of the cavity. We extended an existing Monte Carlo (MC) based light propagation solver to support moving light sources by densely sampling the continuous light source trajectory and assigning the proper number of photon packages launched along the way. The performance of Simphotek GPU CUDA-based implementation of the method - PEDSy-MC - has been demonstrated on a life-size lung-shaped phantom, custom printed for testing icav-PDT navigation system at the Perlman School of Medicine (PSM) - calculations completed under a minute (for some cases) and within minutes have been achieved. We demonstrate results within a 5% error of the analytic solution for multiple detectors in the phantom. PEDSy-MC is accompanied by a dose-cavity visualization tool that allows real-time inspection of dose values of the treated cavity in 2D and 3D, which will be expanded to ongoing clinical trials at PSM. PSM has developed a technology to measure 8-detectors in a pleural cavity phantom using Photofrin-mediated PDT that has been used during validation.

Reactive Oxygen Species Explicit dosimetry for Pleural PDT

This paper starts with definitions of radiance, fluence (rate) and other quantities that are important with regard to in vivo light dosimetry. The light distribution in mammalian tissues can be estimated from model calculations using measured optical properties or from direct measurements of fluence rate using a suitable detector. A historical introduction is therefore followed by a brief discussion of tissue optical properties and of calculations using diffusion theory, the -approximation or Monte Carlo simulations. In particular the form of the scattering function is considered in relation to the fluence rate close to the tissue boundary, where light is incident. Non-invasive measurements of optical properties yield the absorption coefficient and , where is the scattering coefficient and g is the mean cosine of the scattering angle. An important question is whether this combination is sufficient, or whether g itself must be known. It appears that for strongly forward scattering, as in mammalian tissues, rather detailed knowledge of the scattering function is needed to reliably calculate the fluence rate close to the surface. Deeper in the tissue is sufficient. The construction, calibration and use of fibre-optic probes for measurements of fluence rate in tissues or optical phantoms is discussed. At present, minimally invasive absolute fluence (rate) measurements seem to be possible with an accuracy of 10 - 20%. Examples are given of in vivo measurements in animal experiments and in humans during clinical treatments. Measurements in mammalian tissues, plant leaves and marine sediments are compared and similarities and differences pointed out. Most in vivo light fluence rate measurements have been concerned with photodynamic therapy (PDT). Optical properties of the same normal tissue may differ between patients. Tumours of the same histological type may even show different optical properties in a single patient. Treatment-induced changes of optical properties may also occur. Scattered light appears to contribute substantially to the light dose. All these phenomena emphasize the importance of in situ light measurements. Another important dosimetric parameter in PDT is the concentration and distribution of the photosensitizer. Apart from in vivo fluorescence monitoring, the photosensitizer part of in vivo PDT dosimetry is still in its infancy.

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.

Singlet oxygen (1O2) is generally believed to be the major cytotoxic agent during photodynamic therapy (PDT), and the reaction between 1O2 and tumor cells define the treatment efficacy. From a complete set of the macroscopic kinetic equations which describe the photochemical processes of PDT, we can express the reacted 1O2 concentration, [1O2]rx, in a form related to time integration of the product of 1O2 quantum yield and the PDT dose rate. The production of [1O2]rx involves physiological and photophysical parameters which need to be determined explicitly for the photosensitizer of interest. Once these parameters are determined, we expect the computed [1O2]rx to be an explicit dosimetric indicator for clinical PDT. Incorporating the diffusion equation governing the light transport in turbid medium, the spatially and temporally-resolved [1O2]rx described by the macroscopic kinetic equations can be numerically calculated. A sudden drop of the calculated [1O2]rx along with the distance following the decrease of light fluence rate is observed. This suggests that a possible correlation between [1O2]rx and necrosis boundary may occur in the tumor subject to PDT irradiation. In this study, we have theoretically examined the sensitivity of the physiological parameter from two clinical related conditions: (1) collimated light source on semi-infinite turbid medium and (2) linear light source in turbid medium. In order to accurately determine the parameter in a clinical relevant environment, the results of the computed [1O2]rx are expected to be used to fit the experimentally-measured necrosis data obtained from an in vivo animal model.

The Effect of Axial Length on Photodynamic Therapy

Purpose: Establishing the long term stability of laser power measurement in clinic is important for photodynamic therapy. The purpose of this study was to establish the long‐term stability among thermal type power head meters use for laser light fluence and power measurements. Method and Materials: Intercomparison among power meters was performed to determine the consistency of laser power and light fluence rate measured among different power meters. For measurements of power (mW), the beam diameter at the detector surface is smaller than the cross section of the power meter head receiver. For measurement of irradiance (mW/cm2), the light covers the entire aperture of the detector.Results: Power and fluence readings were measured and compared among five detectors, for different laser power settings and wavelengths. For all thermal type power meter suitable for power measurement less than 20W, the calibration of power of different power meters can generally change by 8% among different power meters. However, this calibration does not change over time and remains consistent to within 3% for all power meters. Similar results are obtained for laser fluence rate calibration except for a thermal type power meter head with thick absorbing coating that is suitable for measuring laser power up to 150 W, it's calibration factor can be different from other power meters for as much as 34%, 33% and 31% in fluence calibration, for 532nm, 630nm and 730nm, respectively. It's calibration can vary by over 25% over time. Conclusion: A comparison of power and fluence reading among several power heads used in PDT clinic shows long term consistency for power and light fluence rate calibration to within 3% regardless of wavelength. One should avoid using thermal type power meter head with thick coating, such the LS 150 power meter for light fluence rate calibration.

Purpose: To develop an algorithm used to calculate the fluence rate in real time for intracavitory photodynamic therapy using an infrared (IR) camera tracking system. Method and Materials: Diffusion approximation is used to derive an analytical form of light fluence rate in a spherical cavity inside the cavity and the tissue. The results of our resulting analytical solution are compared with a Finite Element Model (FEM) for the sphere. The FEM method can be used to calculate the fluence rate in tissue in any arbitrary geometries. An light fluence rate calculation algorithm is developed in the chest cavity while taking into account the effect of multiple scattering. We then use a chest phantom and an IR camera system to obtain a 3D map of a chest cavity. This map is then read into our algorithm and the fluence rate is then calculated on the chest surface. We compare our calculations to measured phantom data to determine how accurately our algorithim determines the light fluence in treatment‐like setting. Measurements are made using an in‐situ dosimetry system. Results: Detailed derivation of the light fluence rate in The fluence measurements taken of our chest phantom are currently being analyzed and compared with the fluence rate calculated under the same optical properties from our algorithm. This comparison will help us constrain our algorithm to better fit the observed results and create a more precise treatment planning tool. Conclusion: The work presented here presents the foundation for a valuable new tool in PDT of the pleural cavity in humans. By calculating the fluence rate for patient specific geometries treatment can become more effective and robust. The possibility of developing the work of this paper into a real‐time fluence rate monitoring system provides a new level of exactness in treatment planning for the pleural region.