Evaluation of Light Fluence Distribution Using an IR Navigation System for HPPH-mediated Pleural Photodynamic Therapy (pPDT).

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.

A quality assurance program for clinical PDT.

Successful outcome of Photodynamic therapy (PDT) depends on accurate delivery of prescribed light dose. A quality assurance program is necessary to ensure that light dosimetry is correctly measured. We have instituted a QA program that include examination of long term calibration uncertainty of isotropic detectors for light fluence rate, power meter head intercomparison for laser power, stability of the light-emitting diode (LED) light source integrating sphere as a light fluence standard, laser output and calibration of in-vivo reflective fluorescence and absorption spectrometers. We examined the long term calibration uncertainty of isotropic detector sensitivity, defined as fluence rate per voltage. We calibrate the detector using the known calibrated light fluence rate of the LED light source built into an internally baffled 4″ integrating sphere. LED light sources were examined using a 1mm diameter isotropic detector calibrated in a collimated beam. Wavelengths varying from 632nm to 690nm were used. The internal LED method gives an overall calibration accuracy of ±4%. Intercomparison among power meters was performed to determine the consistency of laser power and light fluence rate measured among different power meters. Power and fluence readings were measured and compared among detectors. A comparison of power and fluence reading among several power heads shows long term consistency for power and light fluence rate calibration to within 3% regardless of wavelength. The standard LED light source is used to calibrate the transmission difference between different channels for the diffuse reflective absorption and fluorescence contact probe as well as isotropic detectors used in PDT dose dosimeter.

Light Fluence Dosimetry in Lung-simulating Cavities.

Accurate light dosimery is critical to ensure consistent outcome for pleural photodynamic therapy (pPDT). Ellipsoid shaped cavities with different sizes surrounded by turbid medium are used to simulate the intracavity lung geometry. An isotropic light source is introduced and surrounded by turbid media. Direct measurements of light fluence rate were compared to Monte Carlo simulated values on the surface of the cavities for various optical properties. The primary component of the light was determined by measurements performed in air in the same geometry. The scattered component was found by submerging the air-filled cavity in scattering media (Intralipid) and absorbent media (ink). The light source was located centrally with the azimuthal angle, but placed in two locations (vertically centered and 2 cm below the center) for measurements. Light fluence rate was measured using isotropic detectors placed at various angles on the ellipsoid surface. The measurements and simulations show that the scattered dose is uniform along the surface of the intracavity ellipsoid geometries in turbid media. One can express the light fluence rate empirically as ϕ =4S/As *Rd/(1 - Rd), where Rd is the diffuse reflectance, As is the surface area, and S is the source power. The measurements agree with this empirical formula to within an uncertainty of 10% for the range of optical properties studied. GPU voxel-based Monte-Carlo simulation is performed to compare with measured results. This empirical formula can be applied to arbitrary geometries, such as the pleural or intraperitoneal cavity.

A summary of light dose distribution using an IR navigation system for Photofrin-mediated Pleural 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. 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.

Real-time treatment light dose guidance of Pleural PDT: an update.

The goal of this study was to develop and improve 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, several 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. Monte-Carlo simulation is used to improve the calculation algorithm for the effect of light that undergoes multiple scattering along the surface in addition to an improvement of the direct light calculation using an improved model that accounts for the anisotropy of the light from the light source.

Determination of tissue optical properties in PDT treated Head & Neck patients.

Determination of optical properties (absorption (µa) and scattering (µs') coefficients) in human tissue is important when it comes to accurate calculation of fluence rate in and around tissue area. ALA application to the tissue induces production of protoporphyrin IX when activated by red light. Changes in the tissue optical properties can send information such as treatment outcome and tissue drug concentration. Patients in this study were treated with PDT for head and neck mucosal dysplasia. They were enrolled in a phase I study of escalating light doses and oral ALA with 60mg/kg. Red light at 630nm was administered to the tumor from a laser. The light dose was escalated from 50-200J/cm2 with a measured fluence rate at tissue surface of 100mW/cm2. We developed a light detection device for the purpose of determining optical properties in vivo using the semi-infinite method. The light detection device consists of two parallel, placed 5mm apart. In one of the catheters a 2 mm long linear diffusing light source is placed while in the second catheter, a calibrated isotropic detector is placed. The detector is scanned along the length of the light source containing catheter. Scans are done with the device placed on the treatment area (tumor) and on the normal tissue. Optical properties were measured in-vivo before and after PDT delivery for both normal tissue and tumor.

Light dosimetry and dose verification for pleural PDT.

In-vivo light dosimetry for patients undergoing photodynamic therapy (PDT) is critical for predicting PDT outcome. Patients in this study are enrolled in a Phase I clinical trial of HPPH-mediated PDT for the treatment of non-small cell lung cancer with pleural effusion. They are administered 4mg per kg body weight HPPH 48 hours before the surgery and receive light therapy with a fluence of 15-45 J/cm2 at 661 and 665nm. Fluence rate (mW/cm2) and cumulative fluence (J/cm2) are monitored at 7 sites during the light treatment delivery using isotropic detectors. Light fluence (rate) delivered to patients is examined as a function of treatment time, volume and surface area. In a previous study, a correlation between the treatment time and the treatment volume and surface area was established. However, we did not include the direct light and the effect of the shape of the pleural surface on the scattered light. A real-time infrared (IR) navigation system was used to separate the contribution from the direct light. An improved expression that accurately calculates the total fluence at the cavity wall as a function of light source location, cavity geometry and optical properties is determined based on theoretical and phantom studies. The theoretical study includes an expression for light fluence rate in an elliptical geometry instead of the spheroid geometry used previously. The calculated light fluence is compared to the measured fluence in patients of different cavity geometries and optical properties. The result can be used as a clinical guideline for future pleural PDT treatment.

In-vivo light dosimetry for HPPH-mediated pleural PDT.

This study examines the light fluence (rate) delivered to patients undergoing pleural PDT as a function of treatment time, treatment volume and surface area. The accuracy of treatment delivery is analyzed as a function of the calibration accuracies of each isotropic detector and the calibration integrating sphere. The patients studied here are enrolled in a Phase I clinical trial of HPPH-mediated PDT for the treatment of non-small cell lung cancer with pleural effusion. Patients are administered 4mg per kg body weight HPPH 24-48 hours before the surgery. Patients undergoing photodynamic therapy (PDT) are treated with light therapy with a fluence of 15-60 J/cm2 at 661nm. Fluence rate (mW/cm2) and cumulative fluence (J/cm2) is monitored at 7 different sites during the entire light treatment delivery. Isotropic detectors are used for in-vivo light dosimetry. The anisotropy of each isotropic detector was found to be within 15%. The mean fluence rate delivery and treatment time are recorded. A correlation between the treatment time and the treatment volume is established. The result can be used as a clinical guideline for future pleural PDT treatment.

In-vivo Light dosimetry for pleural PDT.

In-vivo light dosimetry for patients undergoing photodynamic therapy (PDT) is one of the critical dosimetry quantities for predicting PDT outcome. This study examines the relationship between the PDT treatment time and thoracic treatment volume and surface area for patients undergoing pleural PDT. In addition, the mean light fluence (rate) and its accuracy were quantified. The patients studied here were enrolled in Phase II clinical trial of Photofrin-mediated PDT for the treatment of non-small cell lung cancer with pleural effusion. The ages of the patients studied varied from 34 to 69 years old. All patients were administered 2mg per kg body weight Photoprin 24 hours before the surgery. Patients undergoing photodynamic therapy (PDT) are treated with laser light with a light fluence of 60 J/cm2 at 630nm. 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. The anisotropy of each isotropic detector was found to be within 30%. The mean fluence rate deliver varied from 37.84 to 94.05 mW/cm2 and treatment time varied from 1762 to 5232s. We found a linear correlation between the total treatment time and the treatment area: t (sec) = 4.80 A (cm2). A similar correlation exists between the treatment time and the treatment volume: t (sec) = 2.33 V (cm3). The results can be explained using an integrating sphere theory and the measured tissue optical properties assuming that the saline liquid has a mean absorption coefficient of 0.05 cm-1. Our long term accuracy studies confirmed light fluence rate measurement accuracy of ±10%. The results can be used as a clinical guideline for future pleural PDT treatment.

A heterogeneous algorithm for PDT dose optimization for prostate.

The object of this study is to develop optimization procedures that account for both the optical heterogeneity as well as photosensitizer (PS) drug distribution of the patient prostate and thereby enable delivery of uniform photodynamic dose to that gland. We use the heterogeneous optical properties measured for a patient prostate to calculate a light fluence kernel (table). PS distribution is then multiplied with the light fluence kernel to form the PDT dose kernel. The Cimmino feasibility algorithm, which is fast, linear, and always converges reliably, is applied as a search tool to choose the weights of the light sources to optimize PDT dose. Maximum and minimum PDT dose limits chosen for sample points in the prostate constrain the solution for the source strengths of the cylindrical diffuser fibers (CDF). We tested the Cimmino optimization procedures using the light fluence kernel generated for heterogeneous optical properties, and compared the optimized treatment plans with those obtained using homogeneous optical properties. To study how different photosensitizer distributions in the prostate affect optimization, comparisons of light fluence rate and PDT dose distributions were made with three distributions of photosensitizer: uniform, linear spatial distribution, and the measured PS distribution. The study shows that optimization of individual light source positions and intensities are feasible for the heterogeneous prostate during PDT.

Diffuse reflectance spectra measured in vivo in human tissues during Photofrin-mediated pleural photodynamic therapy.

Optimal delivery of light in photodynamic therapy (PDT) requires not only optimal placement and power of light sources, but knowledge of the dynamics of light propagation in the tissue being treated and in the surrounding normal tissue, and of their respective accumulations of sensitizer. In an effort to quantify both tissue optical properties and sensitizer distribution, we have measured fluorescence emission and diffuse reflectance spectra at the surface of a variety of tissue types in the thoracic cavities of human patients. The patients studied here were enrolled in Phase II clinical trials of Photofrin-mediated PDT for the treatment of non-small cell lung cancer and cancers with pleural effusion. Patients were given Photofrin at dose of 2 mg per kg body weight 24 hours prior to treatment. Each patient received surgical resection of the affected lung and pleura. Patients received intracavity PDT at 630nm to a dose of 30 J/cm2, as determined by isotropic detectors sutured to the cavity walls. We measured the diffuse reflectance spectra before and after PDT in various positions within the cavity, including tumor, diaphragm, pericardium, skin, and chest wall muscle in 5 patients. The measurements we acquired using a specially designed fiber optic-based probe consisting of one fluorescence excitation fiber, one white light delivery fiber, and 9 detection fibers spaced at distances from 0.36 to 7.8 mm from the source, all of which are imaged via a spectrograph onto a CCD, allowing measurement of radially-resolved diffuse reflectance and fluorescence spectra. The light sources for these two measurements (a 403-nm diode laser and a halogen lamp, respectively) were blocked by computer-controlled shutters, allowing sequential fluorescence, reflectance, and background acquisition. The diffuse reflectance was analyzed to determine the absorption and scattering spectra of the tissue and from these, the concentration and oxygenation of hemoglobin and the local drug uptake. The total hemoglobin concentration in normal tissues varied from 50 to 300 µM, and the oxygen saturation was generally above 60%. One tumor measured exhibited higher hemoglobin concentration and lower saturation.

In-vivo light dosimetry of interstitial PDT of human prostate.

We report results of in-vivo light dosimetry of light fluence (rate) in human prostate during photodynamic therapy (PDT). Measurements were made in-vivo at the treatment wavelength (732nm) in 15 patients in three to four quadrants using isotropic detectors placed inside catheters inserted into the prostate. The catheter positions are determined using a transrectal ultrasound (TRUS) unit attached to a rigid template with 0.5-cm resolution. Cylindrical diffusing fibers with various lengths are introduced into the catheters to cover the entire prostate gland. For the last four patients, distributions of light fluence rate along catheters were also measured using a computer controlled step motor system to move multiple detectors to different distances (with 0.1 mm resolution). To predict the light fluence rate distribution, a kernel-based model was used to calculate light fluence rate using either (a) the mean optical properties (assuming homogeneous optical properties) for all patients or (b) using distributions of optical properties measured for latter patients. Standard deviations observed between the calculations and measurements were 56% and 34% for (a) and (b), respectively. The study shows that due to heterogeneity of optical properties significant variations of light fluence rate were observed both intra and inter prostates. However, if one assume a mean optical properties (µa = 0.3 cm-1, µs' = 14 cm-1), one can predict the light fluence rate to within a maximum error 200% for 80% of the cases and a mean error of 105%. To improve the prediction of light fluence rate further would require determination of distribution of optical properties.

Detector Calibration factor for interstitial in-vivo light dosimetry using isotropic detectors with scattering tip.

Isotropic detectors with spherical scattering tips are commonly used for in-vivo dosimetry of light fluence rate during photodynamic therapy (PDT). These detectors are typically calibrated in-air. It has been well established that the response of an isotropic detector is a function of the refractive index (n) of the surrounding medium when it is surrounded by an infinite medium of uniform n. However, there are few, if any, studies of the isotropic detector response when the detector is placed in a secondary medium, such as air, before it is placed inside the infinite uniform medium. This condition often arises when one places the isotropic detector inside an air-filled catheter which is then inserted into a turbid medium, such as tissue. We have performed theoretical and experimental studies to determine the correction factors in water (n = 1.33), which has a refractive index similar to that of tissue (n = 1.4). We found that the resulting correction factor is almost the same (within 20%) as the correction factor for the outermost medium (the water) rather than the immediate medium surrounding the isotropic detector (air). The detector correction factor is also a function of the index of refraction of the probe material. For a 1-mm diameter probe from CardioFocus, the detector correction factor varied from 1 (in air) to 1.09 (at air-water interface) to 1.49 (completely submerged in water). At the air-water interface the spherical bulb of the isotropic detector is placed half in air and half in water. For a 0.5-mm diameter probe from the same company, it varied from 1 (in air) to 1.32 (at air-water interface) to 1.87 (in water). For a 0.3-mm diameter probe from the same company, it varied from 1 (in air) to 1.32 (at air-water interface) to 1.71 (in water). We have also found that the detector response changes by less than 10% when the detector position is varied from touching the catheter wall closest to the light source, to not touching, to touching the catheter wall farthest from the light source. The calibration factors between individual isotropic detectors of the same type varied within 5% for all detector types. Thus mean correction factor can be used for each individual isotropic detector of the same type.

In vivo measurement of fluorescence emission in the human prostate during photodynamic therapy.

Among the challenges to the clinical implementation of photodynamic therapy (PDT) is the delivery of a uniform photodynamic dose to induce uniform damage to the target tissue. As the photodynamic dose depends on both the local sensitizer concentration and the local fluence rate of treatment light, knowledge of both of these factors is essential to the delivery of uniform dose. In this paper, we investigate the distribution and kinetics of the photosensitizer motexafin lutetium (MLu, Lutrin®) as revealed by its fluorescence emission. Our current prostate treatment protocol involves interstitial illumination of the organ via cylindrical diffusing fibers (CDF's) inserted into the prostate though clear catheters. For planning and treatment purposes, the prostate is divided into 4 quadrants. We use one catheter in each quadrant to place an optical fiber-based fluorescence probe into the prostate. This fiber is terminated in a beveled tip, allowing it to deliver and collect light perpendicular to the fiber axis. Excitation light is provided by a 465 nm light emitting diode (LED) source coupled to a dichroic beamsplitter, which passes the collected fluorescence emission to a CCD spectrograph. Spectra are obtained before and after PDT treatment in each quadrant of the prostate and are analyzed via a linear fitting algorithm to separate the MLu fluorescence from the background fluorescence originating in the plastic catheter. A computer-controlled step motor allows the excitation/detection fiber to be moved along the catheter, building up a linear profile of the fluorescence emission spectrum of the tissue as a function of position. We have analyzed spectral fluorescence profiles obtained in 4 patients before and after MLu-mediated PDT. We find significant variation both within individual prostates and among patients. Within a single quadrant, we have observed the fluorescence signal to change by as much as a factor of 3 over a distance of 2 cm. Comparisons of pre- and post-PDT spectra allow a quantification treatment-induced photobleaching. Like the drug distribution, the extent of photobleaching varies widely among patients. In two cases, we observed bleaching of approximately 50% of the drug, while others exhibited negligible photobleaching.

Light Dosimetry at Tissue Surfaces for Oblique Incident Circular Fields.

Oblique incident light fields are sometimes unavoidable for photodynamic therapy of skin cancers, e.g., for large fields on uneven surface. We have performed Monte-Carlo simulation for circular fields (R = 0.25, 0.35, 0.5, 1, 2, 3, and 8 cm) for reduced scattering coefficient µs' = 10 cm-1 and attenuation coefficient µa = 0.1 - 1.0 cm-1. We used anisotropy g = 0.9 and the index of refraction n = 1.4 for all Monte-Carlo simulations. Compared to a broad beam of normal incidence, the peak fluence rate along the central-axis for a slanted beam is increased for otherwise the same geometrical conditions and optical properties. The effective attenuation coefficient is slightly decreased for a slanted beam compared to a normal incident beam. The beam profile for a slanted beam at a fixed depth is no longer symmetrical but is higher towards the lateral side of beam incidence. Since the broad beam with finite radius R can be considered as a convolution of a pencil beam, solution for a slanted pencil beam can be used to determine the light fluence distribution for circular beams with oblique beam incidence. An analytical solution can be obtained for the pencil beam obliquely incident on a semi-infinite medium. The solution can be approximated using the diffusion or P3 theory with one point source or two point sources located at appropriate depths with appropriate weights along the beam pathlength inside the phantom, with corresponding image sources to fulfill the extended boundary condition. The analytical solution agrees well with Monte-Carlo Simulation at depths z > 2cosθ t /µ' t , θt is the incident angle after refraction at the interface. Measurements using an isotropic detector were made in a liquid phantom composed of intralipid and ink to verify the Monte-Carlo simulation results.

Light Dosimetry at Tissue Surfaces for Small Circular Fields.

Small circular light fields (≤ 2 cm diameter) are sometimes used for photodynamic therapy of skin and recurrent breast cancers on the chest wall. These fields have lateral dimensions comparable to the effective mean free path of photons in the turbid medium, which causes reduced light fluence rate compared to that of a broad beam of uniform incident irradiance. We have compared Monte-Carlo simulation with in-vivo dosimetry for circular fields (R = 0.25, 0.35, 0.5, 0.75, 1, 2, 3, and 8 cm) in a liquid phantom composed of intralipid and ink (µs' = 4 - 20 cm-1 and µa = 0.1 cm-1) for wavelengths between 532 and 730 nm. We used anisotropy g = 0.9 and the index of refraction n = 1.4 for all Monte-Carlo simulations. The measured light fluence rate agrees with Monte-Carlo simulation to within 10%, with the measured value lower than that of the Monte-Carlo simulation on tissue surface. The ratio of the peak fluence rates between a circular beam and a broad beam under tissue is 0.58 - 0.96 or 0.84 - 1.00 for R between 0.5 - 2 cm and µeff = 1.1 or 2.0 cm-1, respectively. The ratio of peak fluence rate and incident irradiance for the broad beam is 5.9 and 6.4 for µeff = 1.1 and 2.0 cm-1, respectively. The optical penetration depth δ varies from 0.34 - 0.48 cm for R between 0.5 and 2 cm, with the corresponding δ = 0.51 cm for a broad beam. The ratio of fluence rate and incident irradiance above tissue surface is 1.4 - 1.8 or 1.9 - 2.2 for R between 0.5 - 2 cm and µeff = 1.1 or 2.0 cm-1, respectively. At depth of 0.2 cm inside tissue, Off-axis ratio OAR, defined as the ratio of fluence rate at off-axis distance r to that on the central axis, varies between 0.91 - 0.54 or 0.93 - 0.52 for off-axis distances r between 0.6 and 1.0 cm and µeff = 1.1 or 2.1 cm-1, respectively. In conclusion, in-vivo light dosimetry agrees with Monte-Carlo simulation for small field dosimetry provided the isotropic detector is corrected for the blind spot. The light fluence rates for small circular fields are substantially lower than that of the broad beam of the same incident irradiance.