In vivo fluence rate measurements during Foscan-mediated photodynamic therapy of persistent and recurrent nasopharyngeal carcinomas using a dedicated light applicator

The objective of this study was to evaluate the performance of a dedicated light applicator for light delivery and fluence rate monitoring during Foscan-mediated photodynamic therapy of nasopharyngeal carcinoma in a clinical phase I/II study. We have developed a flexible silicone applicator that can be inserted through the mouth and fixed in the nasopharyngeal cavity. Three isotropic fibers, for measuring of the fluence (rate) during therapy, were located within the nasopharyngeal tumor target area and one was manually positioned to monitor structures at risk in the shielded area. A flexible black silicon patch tailored to the patient's anatomy is attached to the applicator to shield the soft palate and oral cavity from the 652-nm laser light. Fourteen patients were included in the study, resulting in 26 fluence rate measurements in the risk volume (two failures). We observed a systematic reduction in fluence rate during therapy in 20 out of 26 illuminations, which may be related to photodynamic therapy-induced increased blood content, decreased oxygenation, or reduced scattering. Our findings demonstrate that the applicator was easily inserted into the nasopharynx. The average light distribution in the target area was reasonably uniform over the length of the applicator, thus giving an acceptably homogeneous illumination throughout the cavity. Shielding of the risk area was adequate. Large interpatient variations in fluence rate stress the need for in vivo dosimetry. This enables corrections to be made for differences in optical properties and geometry resulting in comparable amounts of light available for Foscan absorption.     

Determination of in vivo light fluence distribution in a heterogeneous prostate during photodynamic therapy

Light fluence delivered to the tumor volume is an important dosimetry quantity in photodynamic therapy (PDT). The in vivo measurements in four patients showed that light fluence rates varied significantly in a prostate during PDT. The maximum and the mean fluence rates in a quadrant varied from 74 to 777 mW cm(-2) and from 45 to 385 mW cm(-2), respectively, among 13 quadrants of four patients' prostates. To determine three-dimensional (3D) light fluence rate distribution in a heterogeneous prostate, a kernel model was developed. The accuracy of the model was examined with a finite-element-method (FEM) model calculation, a phantom measurement, and the in vivo measurements. The kernel model calculations showed good agreements with the FEM model calculation and the measurements. The maximum and the mean deviations of the kernel model calculation from the in vivo measurements in the four patients were 23% and 4%, respectively. The kernel model, which is based on an analytic expression of a point source in a spherically symmetrical heterogeneity, has the advantage of fast calculation and is suitable for real-time PDT treatment planning.     

Light dosimetry for multiple cylindrical diffusing sources for use in photodynamic therapy

Since prostatic carcinoma is usually multifocal within the prostate, effective photodynamic therapy (PDT) of prostatic carcinoma is expected to require the photochemical destruction of the entire organ. Accurate light dosimetry will be essential to avoid damage to proximal sensitive tissue such as the rectum. The prostate will be illuminated using interstitial cylindrical fibreoptic light sources and, because of the limited transparency of prostate tissue, these sources will be mounted in a parallel array analogous to the source array used in brachytherapy. Both source spacing and the light delivered to each source will control light dosimetry from a parallel array of fibreoptic sources implanted into tissue. Clinical PDT will require dose planning in order to determine the position and illumination of each source prior to treatment, but unfortunately few methods of predicting light fluence from cylindrical interstitial sources currently exist. In this paper, a novel light fluence model is used to predict tissue transillumination resulting from cylindrical interstitial sources. The cylindrical source is modelled as a finite array of infinitesimal small sources using Christian Huygens' famous single-slit diffraction model. We show that this source model when combined with a robust derivation of fluence in a spherical geometry using diffusion theory, accurately predicts fluence levels from a single cylindrical source in a variety of media. This method is found to retain its accuracy near the sources. With a simple extension, this fluence model is used to predict the light fluence levels from an array of three sources and the predicted fluence is found to compare favourably with experimental data.     

Carbogen breathing significantly enhances the penetration of red light in murine tumours in vivo

We report results of experiments that evaluated the influence of oxygenation on the penetration of red light in tissue, with particular emphasis on 630 and 650 nm laser wavelengths commonly used in photodynamic therapy (PDT) of solid tumours. Direct measurements in tissue-simulating phantoms comprised of intact human erythrocytes suspended in a scattering emulsion demonstrated significant enhancements in fluence rate at depths of 0.5-2 cm from the irradiated surface when the cells were fully oxygenated versus fully deoxygenated. The 630 and 650 nm fluence rates at depth in the homogeneous phantoms continued to increase when examined over a continuous range of oxygen partial pressures from 0 to 160 Torr. When considered as a function of haemoglobin oxygen saturation, the largest increases in fluence rate were observed as the saturation increased beyond 70%. Dramatic increases in optical fluence rate were measured at the base of 1-cm-thick subcutaneous EMT6 mammary carcinomas in vivo when the tumour-bearing mouse was subjected to carbogen through a nose cone. These results indicate that improved tumour oxygenation is important in PDT not only for the maintenance of the oxygen-dependent photochemistry but, through the effects reported here, may also enable more efficient treatment of thicker lesions.     

Integrating sphere effect in whole bladder wall photodynamic therapy: I. 532 nm versus 630 nm optical irradiation

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.     

Influence of uterine cervix shape on photodynamic therapy efficiency

The goal of practical photodynamic therapy (PDT) dosimetry is to optimize the distribution of a light dose delivered to tissue by selecting the irradiation time and geometry to match the geometry and optical properties of the tumor and surrounding tissue. Homogeneous irradiation is among one of the sources of correct PDT dosimetry. The goal of this study is to model and predict the influence of the shape of a treated organ in need of light dose correction. Thus efficiency of light delivery to the tissue volume is defined and calculated with shape factors of the uterine cervix as parameters. Two cases (parallel and divergent beam) of enlightening configuration are investigated. The calculations presented extend PDT dosimetry with the influence of the shape of the uterine cervix on PDT necrosis depth. This allows for photodynamic excitation light dose correction for more reliable treatments.     

Changes in relative light fluence measured during laser heating: implications for optical monitoring and modelling of interstitial laser photocoagulation

Dynamic changes in internal light fluence were measured during interstitial laser heating of tissue phantoms and ex vivo bovine liver. In albumen phantoms, the results demonstrate an unexpected rise in optical power transmitted approximately I cm away from the source during laser exposure at low power (0.5-1 W), and a decrease at higher powers (1.5-2.5 W) due to coagulation and possibly charring. Similar trends were observed in liver tissue, with a rise in interstitial fluence observed during 0.5 W exposure and a drop in interstitial fluence seen at higher powers (1-1.5 W) due to tissue coagulation. At 1.5 W irradiation an additional, later decrease was also seen which was most likely due to tissue charring. Independent spectrophotometric studies in Naphthol Green dye indicate the rise in fluence observed in the heated albumen phantoms may have been primarily due to light exposure causing photobleaching of the absorbing chromophore. and not due to heat effects. Experiments in liver tissue demonstrated that the observed rise in fluence is dependent on the starting temperature of the tissue. Correlating changes in light fluence with key clinical endpoints/events such as the onset of tissue coagulation or charring may be useful for on-line monitoring and control of laser thermal therapy via interstitial fluence sensors.     

How tissue optics affect dosimetry of photodynamic therapy

We describe three lessons learned about how tissue optics affect the dosimetry of red to near-infrared treatment light during PDT, based on working with Dr. Tayyaba Hasan. Lesson 1-The optical fluence rate φ near the tissue surface exceeds the delivered irradiance (E). A broad beam penetrates into tissue to a depth (z) as φ=Eke(-μz), with an attenuation constant μ and a backscatter term k. In tissues, k is typically in the range 3-5, and 1∕μ equals δ, the 1∕e optical penetration depth. Lesson 2-Edge losses at the periphery of a uniform treatment beam extend about 3δ from the beam edge. If the beam diameter exceeds 6δ, then there is a central zone of uniform fluence rate in the tissue. Lesson 3-The depth of treatment is linearly proportional to δ (and the melanin content of pigmented epidermis in skin) while proportional to the logarithm of all other factors, such as irradiance, exposure time, or the photosensitizer properties (concentration, extinction coefficient, quantum yield for oxidizing species). The lessons illustrate how tissue optics play a dominant role in specifying the treatment zone during PDT.     

Realtime light dosimetry software tools for interstitial photodynamic therapy of the human prostate

Photodynamic therapy (PDT) for the treatment of prostate cancer has been demonstrated to be a safe treatment option capable of inducing tissue destruction and decreasing prostate specific antigen (PSA) levels. However, prostate-PDT results in large intra- and interpatient variations in treatment response, possibly due to biological variations in tissue composition and short-term response to the therapeutic irradiation. Within our group, an instrument for interstitial PDT on prostate tissue has been developed that combines therapeutic light delivery and monitoring of light transmission via numerous bare-ended optical fibers. Here, we present algorithms that utilize data on the light distribution within the target tissue to provide realtime treatment feedback based on a light dose threshold model for PDT. This realtime dosimetry module is implemented to individualize the light dose and compensate for any treatment-induced variations in light attenuation. More specifically, based on the light transmission signals between treatment fibers, spatially resolved spectroscopy is utilized to assess the effective attenuation coefficient of the tissue. These data constitute input to a block-Cimmino optimization algorithm, employed to calculate individual fiber irradiation times provided the requirement to deliver a predetermined light dose to the target tissue while sparing surrounding sensitive organs. By repeatedly monitoring the light transmission signals during the entire treatment session, optical properties and individual fiber irradiation times are updated in realtime. The functionality of the algorithms is tested on diffuse light distribution data simulated by means of the finite element method (FEM). The feasibility of utilizing spatially resolved spectroscopy within heterogeneous media such as the prostate gland is discussed. Furthermore, we demonstrate the ability of the block-Cimmino algorithm to discriminate between target tissue and organs at risk (OAR). Finally, the realtime dosimetry module is evaluated for treatment scenarios displaying spatially and temporally varying light attenuation levels within the target tissue. We conclude that the realtime dosimetry module makes it possible to deliver a certain light dose to the target tissue despite spatial and temporal variations of the target tissue optical properties at the therapeutic wavelength.     

Transperineal in vivo fluence-rate dosimetry in the canine prostate during SnET2-mediated PDT

Advances in photodynamic therapy (PDT) treatment for prostate cancer can be achieved either by improving selectivity of the photosensitizer towards prostate gland tissue or improving the dosimetry by means of individualized treatment planning using currently available photosensitizers. The latter approach requires the ability to measure, among other parameters, the fluence rate at different positions within the prostate and the ability to derive the tissue optical properties. Here fibre optic probes are presented capable of measuring the fluence rate throughout large tissue volumes and a method to derive the tissue optical properties for different volumes of the prostate. The responsivity of the sensors is sufficient to detect a fluence rate of 0.1 mW cm(-2). The effective attenuation coefficient in the canine prostate at 660 nm is higher at the capsule (2.15+/-0.19 cm(-1)) than in proximity of the urethra (1.84+/-0.36 cm(-1)). Significant spatial and temporal intra- and inter-canine variability in the tissue optical properties was noted, highlighting the need for individualized monitoring of the fluence rate for improved dosimetry.     

Performance of isotropic light dosimetry probes based on scattering bulbs in turbid media

In a previous paper the calibration of an isotropic light detector in clear media was described and validated. However, in most applications the detector is used to measure light distribution in turbid (scattering) media, that is, in tissues or tissue equivalent optical phantoms. Despite its small diameter (typically 0.8 mm), inserting the detector in a turbid medium may perturb the light distribution and change the fluence rate at the point of measurement. In the present paper we estimate the error in the fluence rate measured by a detector in turbid media after calibration in a clear medium (air), using an optical phantom and detector bulbs of different optical properties. The experimental results are compared with calculations using the diffusion approximation to the transport equation in a spherical geometry. From measurements in optical phantoms and the results of the calculations it appears that introduction of the detector into a water-based turbid medium with refractive index, absorption- and scattering coefficients different from those of the detector bulb may require corrections to the detector response of up to 10-15%, in order to obtain the true fluence rate in that medium. The diffusion model is used to explore the detector response in a number of tissues of interest in photodynamic therapy, using tissue optical properties from the literature. Based on these model calculations it is estimated that in real tissues the fluence rate measured by the detector is up to 3% below the true value.     

System for interstitial photodynamic therapy with online dosimetry: first clinical experiences of prostate cancer

The first results from a clinical study for Temoporfin-mediated photodynamic therapy (PDT) of low-grade (T1c) primary prostate cancer using online dosimetry are presented. Dosimetric feedback in real time was applied, for the first time to our knowledge, in interstitial photodynamic therapy. The dosimetry software IDOSE provided dose plans, including optical fiber positions and light doses based on 3-D tissue models generated from ultrasound images. Tissue optical property measurements were obtained using the same fibers used for light delivery. Measurements were taken before, during, and after the treatment session. On the basis of these real-time measured optical properties, the light-dose plan was recalculated. The aim of the treatment was to ablate the entire prostate while minimizing exposure to surrounding organs. The results indicate that online dosimetry based on real-time tissue optical property measurements enabled the light dose to be adapted and optimized. However, histopathological analysis of tissue biopsies taken six months post-PDT treatment showed there were still residual viable cancer cells present in the prostate tissue sections. The authors propose that the incomplete treatment of the prostate tissue could be due to a too low light threshold dose, which was set to 5 J∕cm2.     

Immune response against angiosarcoma following lower fluence rate clinical photodynamic therapy.

Tumor response to photodynamic therapy (PDT) is dependent on treatment parameters used. In particular, the light fluence rate may be an important determinant of the treatment outcome. In this clinical case report, we describe the response of angiosarcoma to PDT carried out using different fluence rates and drug and light doses. A patient with recurrent multifocal angiosarcoma of the head and neck was recruited for PDT. A new generation chlorin-based photosensitizer, Fotolon, was administered at a dose of 2.0 to 5.7 mg/kg. The lesions were irradiated with 665 nm laser light for a light dose of 65 to 200 J/cm2 delivered at a fluence rate of 80 or 150 mW/cm2. High dose PDT carried out at a high fluence rate resulted in local control of the disease for up to a year; however, the disease recurred and PDT had to be repeated. PDT of new lesions carried out at a lower fluence rate resulted in tumor eradication. More significantly, it also resulted in spontaneous remission of neighboring and distant untreated lesions. Repeat PDT carried out on a recurrent lesion at a lower fluence rate resulted in eradication of both treated and untreated lesions despite the lower total light dose delivered. Immunohistochemical examination of biopsy samples implies that PDT could have activated a cell-mediated immune response against untreated lesions. Subsequent histopathological examination of the lesion sites showed negative for disease. Our clinical observations show that lower fluence rate PDT results in better outcome and also indicate that the fluence rate, rather than the total light dose, is a more crucial determinant of the treatment outcome. Specifically, lower fluence rate PDT appears to activate the body's immune response against untreated lesions.     

Determination of optical properties in heterogeneous turbid media using a cylindrical diffusing fiber

For interstitial photodynamic therapy (PDT), cylindrical diffusing fibers (CDFs) are often used to deliver light. This study examines the feasibility and accuracy of using CDFs to characterize the absorption (μ(a)) and reduced scattering (μ'(s)) coefficients of heterogeneous turbid media. Measurements were performed in tissue-simulating phantoms with μ(a)?between 0.1 and 1?cm(-1)?and μ'(s) between 3 and 10?cm(-1)?with CDFs 2 to 4?cm in length. Optical properties were determined by fitting the measured light fluence rate profiles at a fixed distance from the CDF axis using a heterogeneous kernel model in which the cylindrical diffusing fiber is treated as a series of point sources. The resulting optical properties were compared with independent measurement using a point source method. In a homogenous medium, we are able to determine the absorption coefficient μ(a)?using a value of μ'(s) determined a priori (uniform fit) or μ'(s) obtained by fitting (variable fit) with standard (maximum) deviations of 6% (18%) and 18% (44%), respectively. However, the CDF method is found to be insensitive to variations in μ'(s), thus requiring a complementary method such as using a point source for determination of μ'(s). The error for determining μ(a)?decreases in very heterogeneous turbid media because of the local absorption extremes. The data acquisition time for obtaining the one-dimensional optical properties distribution is less than 8?s. This method can result in dramatically improved accuracy of light fluence rate calculation for CDFs for prostate PDT in vivo when the same model and geometry is used for forward calculations using the extrapolated tissue optical properties.     

Novel flexible light diffuser and irradiation properties for photodynamic therapy

Many current light diffusers for photodynamic therapy are inflexible, and the applied light dose is difficult to adjust during treatment, especially on complex body surfaces. A thin and flexible luminous textile is developed using plastic optical fibers as a light distributor. The textile diffuser is evaluated for flexibility, irradiance, brightness distribution, and temperature rise with a 652-nm laser set to 100 mW. The bending force of the textile diffuser resembles a defined optical film. On the textile surface, an average output power of 3.6+/-0.6 mWcm(2) is measured, corresponding to a transmission rate of 40+/-3.8% on an area of 11 cm(2). Aluminum backing enhances the irradiance to the face (treatment side). The measured brightness distribution seems to lie within a range similar to other photodynamic therapy (PDT) devices. A power setting of 100 mW increases the temperature of the textile diffuser surface of up to 27 degrees C, and 1 W raises the temperature above 40 degrees C. Results confirm that the flexible textile diffuser supplies suitable radiation for low fluence rate photodynamic therapy on an area of several cm(2).     

Design, development, and implementation of the radiological physics center's pelvis and thorax anthropomorphic quality assurance phantoms

The Radiological Physics Center (RPC) developed two heterogeneous anthropomorphic quality assurance phantoms for use in verifying the accuracy of radiation delivery: one for intensity-modulated radiation therapy (IMRT) to the pelvis and the other for stereotactic body radiation therapy (SBRT) to the thorax. The purpose of this study was to describe the design and development of these two phantoms and to demonstrate the reproducibility of measurements generated with them. The phantoms were built to simulate actual patient anatomy. They are lightweight and water-fillable, and they contain imageable targets and organs at risk of radiation exposure that are of similar densities to their human counterparts. Dosimetry inserts accommodate radiochromic film for relative dosimetry and thermoluminesent dosimetry capsules for absolute dosimetry. As a part of the commissioning process, each phantom was imaged, treatment plans were developed, and radiation was delivered at least three times. Under these controlled irradiation conditions, the reproducibility of dose delivery to the target TLD in the pelvis and thorax phantoms was 3% and 0.5%, respectively. The reproducibility of radiation-field localization was less than 2.5 mm for both phantoms. Using these anthropomorphic phantoms, pelvic IMRT and thoracic SBRT radiation treatments can be verified with a high level of precision. These phantoms can be used to effectively credential institutions for participation in specific NCI-sponsored clinical trials.     

Monte Carlo simulations of the use of isotropic light dosimetry probes to monitor energy fluence in biological tissues

The use of isotropic light dosimetry probes is being increasingly advocated to monitor the light dose during photodynamic therapy. In this paper Monte Carlo simulations were used to study the potential error resulting from the disturbance of the local fluence due to presence of the probe. External irradiation of a plane slab of tissue was modelled for two sets of tissue optical properties. A highly scattering, nearly spherical detector probe, approximately 1 mm in diameter, positioned just above the tissue surface and at several depths below the surface, was incorporated into the simulation. Tissue fluence distributions were generated in the absence of the detector probe, and with the probe in situ. The presence of the probe caused negligible disturbance to the ambient fluence distribution when embedded in the tissue. The fluence measured at the centre of the detector probe showed a good correlation with the tissue fluence measured in the absence of the probe. With the detector probe positioned just above the tissue surface some reduction in surface tissue fluence was observed, although this effect was negligible at greater tissue depths. It was concluded that, when embedded in tissue, isotropic detector probes produce an accurate measure of tissue fluence or fluence rate.     

Protoporphyrin IX fluorescence photobleaching increases with the use of fractionated irradiation in the esophagus

Fluorescence measurements have been used to track the dosimetry of photodynamic therapy (PDT) for many years, and this approach can be especially important for treatments with aminolevulinic-acid-induced protoporphyrin IX (ALA-PpIX). PpIX photobleaches rapidly, and the bleaching is known to be oxygen dependent, and at the same time, fractionation or reduced irradiance treatments have been shown to significantly increase efficacy. Thus, in vivo measurement of either the bleaching rate and/or the total bleaching yield could be used to track the deposited dose in tissue and determine the optimal treatment plans. Fluorescence in rat esophagus and human Barrett's esophagus are measured during PDT in both continuous and fractionated light delivery treatment, and the bleaching is quantified. Reducing the optical irradiance from 50 to 25 mWcm did not significantly alter photobleaching in rat esophagus, but fractionation of the light at 1-min on and off intervals did increase photobleaching up to 10% more (p value=0.02) and up to 25% more in the human Barrett's tissue (p value<0.001). While two different tissues and two different dosimetry systems are used, the data support the overall hypothesis that light fractionation in ALA-PpIX PDT esophageal treatments should have a beneficial effect on the total treatment effect.     

Integrating spheres for improved skin photodynamic therapy

The prescribed radiant exposures for photodynamic therapy (PDT) of superficial skin cancers are chosen empirically to maximize the success of the treatment while minimizing adverse reactions for the majority of patients. They do not take into account the wide range of tissue optical properties for human skin, contributing to relatively low treatment success rates. Additionally, treatment times can be unnecessarily long for large treatment areas if the laser power is not sufficient. Both of these concerns can be addressed by the incorporation of an integrating sphere into the irradiation apparatus. The light fluence rate can be increased by as much as 100%, depending on the tissue optical properties. This improvement can be determined in advance of treatment by measuring the reflectance from the tissue through a side port on the integrating sphere, allowing for patient-specific treatment times. The sphere is also effective at improving beam flatness, and reducing the penumbra, creating a more uniform light field. The side port reflectance measurements are also related to the tissue transport albedo, enabling an approximation of the penetration depth, which is useful for real-time light dosimetry.     

In vivo measurement of the optical interaction coefficients of human tumours at 630 nm

The light distribution within a treatment volume is determined by the source geometry (e.g. superficial or interstitial illumination) and the optical interaction coefficients of the irradiated tissue. We have measured the energy fluence rate at various points within tumours undergoing irradiation with 630 nm light for photodynamic therapy for several source geometries. The relative positions of source and detector fibres were determined using CT scanning techniques. The results of the measurements were then applied to solutions of the diffusion theory which allowed the determination of the absorption coefficient (sigma a = 30.5 +/- 16 m-1), the reduced scattering coefficient (sigma' s = 941 +/- 735 m-1), the effective attenuation coefficient (sigma eff = 261 +/- 49 m-1) and the build-up coefficient which relates surface irradiance to the energy fluence rate at depth (k = 1.6 +/- 0.6). Knowledge of these coefficients allows the transmission of light through tissue to be predicted and hence the optical dosimetry of subsequent treatments to be planned more effectively.