Infrared navigation system for light dosimetry during pleural photodynamic therapy.

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%.

In vivo Spectroscopic Evaluation of the Intraperitoneal Cavity in Canines.

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.

Light Fluence Rate and Tissue Oxygenation (St O2 ) Distributions Within the Thoracic Cavity of Patients Receiving Intraoperative Photodynamic Therapy for Malignant Pleural Mesothelioma.

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.

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.

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.

Monte Carlo modelling of fluorescence in semi-infinite turbid media.

The incident field size and the interplay of absorption and scattering can influence the in-vivo light fluence rate distribution and complicate the absolute quantification of fluorophore concentration in-vivo. In this study, we use Monte Carlo simulations to evaluate the effect of incident beam radius and optical properties to the fluorescence signal collected by isotropic detector placed on the tissue surface. The optical properties at the excitation and emission wavelengths are assumed to be identical. We compute correction factors to correct the fluorescence intensity for variations due to incident field size and optical properties. The correction factors are fitted to a 4-parameters empirical correction function and the changes in each parameter are compared for various beam radius over a range of physiologically relevant tissue optical properties (µa = 0.1 - 1 cm-1, µs'= 5 - 40 cm-1).

Determination of optical properties, drug concentration, and tissue oxygenation in human pleural tissue before and after Photofrin-mediated photodynamic therapy.

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 µa (λ) and scattering µs ' (λ) coefficients), photofrin concentration (cphotofrin), blood oxygen saturation (%StO2), 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.

Radiotherapy fiber dosimeter probes based on silver-only coated hollow glass waveguides.

Manifestation of Cerenkov radiation as a contaminating signal is a significant issue in radiation therapy dose measurement by fiber-coupled scintillator dosimeters. To enhance the scintillation signal transmission while minimizing Cerenkov radiation contamination, we designed a fiber probe using a silver-only coated hollow waveguide (HWG). The HWG with scintillator inserted in its tip, embedded in tissue-mimicking phantoms, was irradiated with clinical electron and photon beams generated by a medical linear accelerator. Optical spectra of the irradiated tip were taken using a fiber spectrometer, and the signal was deconvolved with a linear fitting algorithm. The resultant decomposed spectra of the scintillator with and without Cerenkov correction were in agreement with measurements performed by a standard electron diode and ion chamber for electron and photon beam dosimetry, respectively, indicating the minimal effect of Cerenkov contamination in the HWG-based dosimeter. Furthermore, compared with a silver/dielectric-coated HWG fiber dosimeter design, we observed higher signal transmission in the design based on the use of silver-only HWG.

Lesion oxygenation associates with clinical outcomes in premalignant and early stage head and neck tumors treated on a phase 1 trial of photodynamic therapy.

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.

PDT dose dosimetry for Photofrin-mediated pleural photodynamic therapy (pPDT).

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.

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.

Proton therapy dosimetry using the scintillation of the silica fibers.

We investigate the feasibility of proton therapy dose measurement by using scintillation of a bare silica glass fiber. The emission spectra of the optical fiber at various depths in tissue-mimicking phantoms, irradiated with proton beams of energies 100-225 MeV show two distinct peaks at 460 and 650 nm whose nature is connected with the silica point defects. Our experimental results and Monte Carlo simulation showed that the Cerenkov radiation cannot be responsible for such a phenomenon. We showed that the intensity of the peak at 650 nm correlates with the proton dose with a minimal effect of ionization quenching, while the intensity peak at 460 nm under-reports the radiation dose.

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.

The visible signal responsible for proton therapy dosimetry using bare optical fibers is not Cerenkov radiation.

PURPOSE: Proton beam dosimetry using bare plastic optical fibers has emerged as a simple approach to proton beam dosimetry. The source of the signal in this method has been attributed to Cerenkov radiation. The aim of this work was a phenomenological study of the nature of the visible light responsible for the signal in bare fiber optic dosimetry of proton therapy beams. METHODS: Plastic fiber optic probes embedded in solid water phantoms were irradiated with proton beams of energies 100, 180, and 225 MeV produced by a proton therapy cyclotron. Luminescence spectroscopy was performed by a CCD-coupled spectrometer. The spectra were acquired at various depths in phantom to measure the percentage depth dose (PDD) for each beam energy. For comparison, the PDD curves were acquired using a standard multilayer ion chamber device. In order to further analyze the contribution of the Cerenkov radiation in the spectra, Monte Carlo simulation was performed using fluka Monte Carlo code to stochastically simulate radiation transport, ionizing radiation dose deposition, and optical emission of Cerenkov radiation. RESULTS: The measured depth doses using the bare fiber are in agreement with measurements performed by the multilayer ion chamber device, indicating the feasibility of using bare fiber probes for proton beam dosimetry. The spectroscopic study of proton-irradiated fibers showed a continuous spectrum with a shape different from that of Cerenkov radiation. The Monte Carlo simulations confirmed that the amount of the generated Cerenkov light does not follow the radiation absorbed dose in a medium. CONCLUSIONS: The source of the optical signal responsible for the proton dose measurement using bare optical fibers is not Cerenkov radiation. It is fluorescence of the plastic material of the fiber.

Investigating the impact of oxygen concentration and blood flow variation on photodynamic therapy.

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 automated electronic system for managing radiation treatment plan peer review reduces missed reviews at a large, high-volume academic center.

BACKGROUND: Assuring quality in cancer care through peer review has become increasingly important in radiation oncology. In 2012, our department implemented an automated electronic system for managing radiation treatment plan peer review. The purpose of this study was to compare the overall impact of this electronic system to our previous manual, paper-based system. METHODS AND MATERIALS: In an effort to improve management, an automated electronic system for case finding and documentation of review was developed and implemented. The rates of missed initial reviews, late reviews, and missed re-reviews were compared for the pre- versus postelectronic system cohorts using Pearson χ2 test and relative risk. Major and minor changes or recommendations were documented and shared with the assigned clinical provider. RESULTS: The overall rate of missed reviews was 7.6% (38/500) before system implementation versus 0.4% (28/6985) under the electronic system (P < .001). In terms of relative risk, courses were 19.0 times (95% confidence interval, 11.8-30.7) more likely to be missed for initial review before the automated system. Missed re-reviews occurred in 23.1% (3/13) of courses in the preelectronic system cohort and 6.6% (10/152) of courses in the postelectronic system cohort (P = .034). Late reviews were more frequent during high travel or major holiday periods. Major changes were recommended in 2.2% and 2.8% in the pre- versus postelectronic systems, respectively. Minor changes were recommended in 5.3% of all postelectronic cases. CONCLUSIONS: The implementation of an automated electronic system for managing peer review in a large, complex department was effective in significantly reducing the number of missed reviews and missed re-reviews when compared to our previous manual system.

PDT Dose Dosimeter for Pleural Photodynamic Therapy.

PDT dose is the product of the photosensitizer concentration and the light fluence in the target tissue. For improved dosimetry during plural photodynamic therapy (PDT), a PDT dose dosimeter was developed to measure both the light fluence and the photosensitizer concentration simultaneously in the same treatment location. Light fluence and spectral data were rigorously compared to other methods of measurement (e.g. photodiode, multi-fiber spectroscopy contact probe) to assess the accuracy of the measurements as well as their uncertainty. Photosensitizer concentration was obtained by measuring the fluorescence of the sensitizer excited by the treatment light. Fluence rate based on the intensity of the laser spectrum was compared to the data obtained by direct measurement of fluence rate by a fiber-coupled photodiode. Phantom studies were done to obtain an optical property correction for the fluorescence signal. Measurements were performed in patients treated Photofrin for different locations in the pleural cavity. Multiple sites were measured to investigate the heterogeneity of the cavity and to provide cross-validation via relative dosimetry. This novel method will allow for accurate real-time determination of delivered PDT dose and improved PDT dosimetry.

Deformable medical image registration of pleural cavity for photodynamic therapy by using finite-element based method.

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.

Toxicities and early outcomes in a phase 1 trial of photodynamic therapy for premalignant and early stage head and neck tumors.

OBJECTIVES: Management of early superficial lesions in the head and neck remains complex. We performed a phase 1 trial for high-grade premalignant and early superficial lesions of the head and neck using photodynamic therapy (PDT) with Levulan (ALA). MATERIALS AND METHODS: Thirty-five subjects with high grade dysplasia, carcinoma in situ, or microinvasive (⩽1.5mm depth) squamous cell carcinoma were enrolled. Cohorts of 3-6 patients were given escalating intraoperative light doses of 50-200J/cm(2) 4-6h after oral administration of 60mg/kg ALA. Light at 629-635nm was delivered in a continuous (unfractionated) or fractionated (two-part) schema. RESULTS: PDT was delivered to 30/35 subjects, with 29 evaluable. There was one death possibly due to the treatment. The regimen was otherwise tolerable, with a 52% rate of grade 3 mucositis which healed within several weeks. Other toxicities were generally grade 1 or 2, including odynophagia (one grade 4), voice alteration (one grade 3), and photosensitivity reactions. One patient developed grade 5 sepsis. With a median follow-up of 42months, 10 patients (34%) developed local recurrence; 4 of these received 50J/cm(2) and two each received 100, 150, and 200J/cm(2). Ten (34%) patients developed recurrence adjacent to the treated field. There was a 69% complete response rate at 3months. CONCLUSIONS: ALA-PDT is well tolerated. Maximum Tolerated Dose appears to be higher than the highest dose used in this study. Longer followup is required to analyze effect of light dose on local recurrence. High marginal recurrence rates suggest use of larger treatment fields.

Spectroscopic separation of Cerenkov radiation in high-resolution radiation fiber dosimeters.

We have investigated Cerenkov radiation generated in phosphor-based optical fiber dosimeters irradiated with clinical electron beams. We fabricated two high-spatial resolution fiber-optic probes, with 200 and 400 µm core diameters, composed of terbium-based phosphor tips. A generalizable spectroscopic method was used to separate Cerenkov radiation from the transmitted signal by the fiber based on the assumption that the recorded signal is a linear superposition of two basis spectra: characteristic luminescence of the phosphor medium and Cerenkov radiation. We performed Monte Carlo simulations of the Cerenkov radiation generated in the fiber and found a strong dependence of the recorded Cerenkov radiation on the numerical aperture of the fiber at shallow phantom depths; however, beyond the depth of maximum dose that dependency is minimal. The simulation results agree with the experimental results for Cerenkov radiation generated in fibers. The spectroscopic technique used in this work can be used for development of high-spatial resolution fiber micro dosimeters and for optical characterization of various scintillating materials, such as phosphor nanoparticles, in ionizing radiation fields of high energy.