Evaluation of Detector Position and Light Fluence Distribution Using an Infrared Navigation System during Pleural Photodynamic Therapy†.

Photodynamic therapy (PDT) has been used to treat malignant pleural mesothelioma. Current practice involves delivering light to a prescribed light fluence with a point source, monitored by eight isotropic detectors inside the pleural cavity. An infrared (IR) navigation system was used to track the location of the point source throughout the treatment. The recorded data were used to reconstruct the pleural cavity and calculate the light fluence to the whole cavity. An automatic algorithm was developed recently to calculate the detector positions based on recorded data within an hour. This algorithm was applied to patient case studies and the calculated results were compared to the measured positions, with an average difference of 2.5 cm. Calculated light fluence at calculated positions were compared to measured values. The differences between the calculated and measured light fluence were within 14% for all cases, with a fixed scattering constant and a dual correction method. Fluence-surface histogram (FSH) was calculated for photofrin-mediated PDT to be able to cover 80% of pleural surface area to 50 J cm-2 (83.3% of 60 J cm-2 ). The study demonstrates that it will be possible to eliminate the manual measurement of the detector positions, reducing the patient's time under anesthesia.

Light Sources and Dosimetry Techniques for Photodynamic Therapy.

Effective treatment delivery in photodynamic therapy (PDT) requires coordination of the light source, the photosensitizer, and the delivery device appropriate to the target tissue. Lasers, light-emitting diodes (LEDs), and lamps are the main types of light sources utilized for PDT applications. The choice of light source depends on the target location, photosensitizer used, and light dose to be delivered. Geometry of minimally accessible areas also plays a role in deciding light applicator type. Typically, optical fiber-based devices are used to deliver the treatment light close to the target. The optical properties of tissue also affect the distribution of the treatment light. Treatment light undergoes scattering and absorption in tissue. Most tissue will scatter light, but highly pigmented areas will absorb light, especially at short wavelengths. This review will summarize the basic physics of light sources, and describe methods for determining the dose delivered to the patient.

Reactive Oxygen Species Explicit Dosimetry for Photofrin-mediated Pleural Photodynamic Therapy.

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 intraoperatively 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 × 109 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 intrapatient heterogeneities in [ROS]rx were observed although an identical light dose of 60 J cm-2 was prescribed to all patients.

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.

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.

A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin-mediated Photodynamic Therapy.

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.

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.

Parameter Determination for Singlet Oxygen Modeling of BPD-Mediated PDT.

Photodynamic therapy (PDT) offers a cancer treatment modality capable of providing minimally invasive localized tumor necrosis. To accurately predict PDT treatment outcome based on pre-treatment patient specific parameters, an explicit dosimetry model is used to calculate apparent reacted 1O2 concentration ([1O2]rx) at varied radial distances from the activating light source inserted into tumor tissue and apparent singlet oxygen threshold concentration for necrosis ([1O2]rx, sd) for type-II PDT photosensitizers. Inputs into the model include a number of photosensitizer independent parameters as well as photosensitizer specific photochemical parameters ξ, σ, and ß. To determine the specific photochemical parameters of benzoporphyrin derivative monoacid A (BPD), mice were treated with BPD-PDT with varied light source strengths and treatment times. All photosensitizer independent inputs were assessed pre-treatment and average necrotic radius in treated tissue was determined post-treatment. Using the explicit dosimetry model, BPD specific ξ, σ, and ß photochemical parameters were determined which estimated necrotic radii similar to those observed in initial BPD-PDT treated mice using an optimization algorithm that minimizes the difference between the model and that of the measurements. Photochemical parameters for BPD are compared with those of other known photosensitizers, such as Photofrin. The determination of these BPD specific photochemical parameters provides necessary data for predictive treatment outcome in clinical BPD-PDT using the explicit dosimetry model.