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.     

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.     

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.     

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.     

Wedge-shaped applicator for additional light delivery and dosimetry in the diaphragmal sinus during photodynamic therapy for malignant pleural mesothelioma

In situ light dosimetry during photodynamic therapy (PDT) of malignant pleural mesothelioma (MPM) after tumour resection facilitates the delivery of a controlled light distribution to the inner thoracic surface. Illumination of the diaphragm-induced sinus, however, remains difficult. Our aim was to develop a wedge-shaped light applicator with incorporated light dosimetry to deliver an additional fluence limited to the sinus. The wedge-shaped applicator contains a cylindrical diffuser for light delivery and two isotropic detectors for simultaneous light dosimetry. These detectors were placed at strategic positions where the fluence rate is maximal or minimal (middle and edge). Prior to its clinical use, the performance of the sinus light applicator was tested in several optical tissue phantoms with different optical properties. The fluence rate distribution over the surface of the applicator showed little change when the wedge was submerged in four different optical phantoms. During clinical PDT of MPM the applicator had to be re-located manually four times in order to give an additional fluence of approximately 2 J cm(-2) to the entire sinus. The light applicator enables dosimetry-controlled light delivery for additional illumination of the sinus region that is often under-illuminated during thoracic integral illumination of MPM.     

Determination of the tumor tissue optical properties during and after photodynamic therapy using inverse Monte Carlo method and double integrating sphere between 350 and 1000 nm

Photodynamic therapy (PDT) efficacy depends on the amount of light distribution within the tissue. However, conventional PDT does not consider the laser irradiation dose during PDT. The optical properties of biological tissues (absorption coefficient μ(a), reduced scattering coefficient μ's), anisotropy factor g, refractive index, etc.) help us to recognize light propagation through the tissue. The goal of this paper is to acquire the knowledge of the light propagation within tissue during and after PDT with the optical property of PDT-performed mouse tumor tissue. The optical properties of mouse tumor tissues were evaluated using a double integrating sphere setup and the algorithm based on the inverse Monte Carlo method in the wavelength range from 350 to 1000 nm. During PDT, the μ(a) and μ's were not changed after 1 and 5 min of irradiation. After PDT, the μ's in the wavelength range from 600 to 1000 nm increased with the passage of time. For seven days after PDT, the μ's increased by 1.7 to 2.0 times, which results in the optical penetration depth decreased by 1.4 to 1.8 times. To ensure an effective procedure, the adjustment of laser parameters for the decreasing penetration depth is recommended for the re-irradiation of PDT.     

Monitoring singlet oxygen in situ with delayed chemiluminescence to deduce the effect of photodynamic therapy

Singlet oxygen ((1)O(2)) is an important factor mediating cell killing in photodynamic therapy (PDT). We previously reported that chemiluminescence (CL) can be used to detect (1)O(2) production in PDT and linked the signal to the PDT-induced cytotoxicity in vitro. We develop a new CL detection apparatus to achieve in vivo measurements. The system utilizes a time-delayed CL signal to overcome the interference from scattered excitation light, thus greatly improving the accuracy of the detection. The system is tested on healthy skin of BALB/ca mouse for its feasibility and reliability. The CL measurement is made during a synchronized gating period of the irradiation light. After each PDT treatment and in situ CL measurement, the skin response is scored over a period of 2 weeks. A remarkable relationship is observed between the score and the CL, regardless of the PDT treatment protocol. Although there are many issues yet to be addressed, our results clearly demonstrate the feasibility of CL measurement during PDT and its potential for in vivo PDT dosimetry. This requires further investigations.     

Photodynamic dose does not correlate with long-term tumor response to mTHPC-PDT performed at several drug-light intervals

Meso-tetra-hydroxyphenyl-chlorin (mTHPC, Foscan), a promising photosensitizer for photodynamic therapy (PDT), is approved in Europe for the palliative treatment of head and neck cancer. Based on work in mice that investigated optimal tumor accumulation, clinical protocols with Foscan typically employ an interval of 96 h between systemic sensitizer administration and irradiation. However, recent studies in mouse tumor models have demonstrated significantly improved long-term tumor response when irradiation is performed at shorter drug-light intervals of 3 and 6 h. Using a previously published theoretical model of microscopic PDT dosimetry and informed by experimentally determined photophysical properties and intratumor sensitizer concentrations and distributions, we calculated photodynamic dose depositions following mTHPC-PDT for drug-light intervals of 3, 6, 24, and 96 h. Our results demonstrate that the singlet oxygen dose to the tumor volume does not track even qualitatively with tumor responses for these four drug-light intervals. Further, microscopic analysis of simulated singlet oxygen deposition shows that in no case do any subpopulations of tumor cells receive a threshold dose. Indeed, under the conditions of these simulations more than 90% of the tumor volume receives a dose that is approximately 20-fold lower than the threshold dose for mTHPC. Thus, in this evaluation of mTHPC-PDT at various drug-light intervals, any PDT dose metric that is proportional to singlet oxygen creation and/or deposition would fail to predict the tumor response. In situations like this one, other reporters of biological response to therapy would be necessary.     

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.     

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.     

Absorbed dose dependence of the correction factors for ionization chamber cable irradiation effects

A simple method was developed, for possible use by hospital physicists, to evaluate the irradiation effects on cables and connectors during large-radiation-field dosimetry with ionization chambers and to determine correction factors for the used system or geometry. This method was based on the absorbed dose dependence of the correction factor.     

兔原位直肠癌的光动力治疗效应和不良反应研究

目的 以兔原位直肠癌为动物模型,探讨内镜光动力疗法在治疗腔道肿瘤时照光剂量、操作方法、不良反应等对其疗效的影响,为光动力疗法治疗直肠癌提供临床前依据.方法 建立20只兔VX2原位直肠癌模型,随机分为对照组、PDT低剂量组、PDT中剂量组和PDT高剂量组.血卟啉单甲醚(HMME)光敏剂于PDT前24 h静脉注射兔体内.光源采用630 nm半导体激光器.使用普通内镜和超声内镜观察肿瘤生长情况,并记录生存时间、一般状况、不良反应等.使用苏木精-伊红染色法染色并观察组织病理变化.结果 PDT后第7天,PDT低剂量组40％轻度有效;PDT中剂量组60％明显有效,20％轻度有效;PDT高剂量组20％明显有效,80％轻度有效.PDT低剂量、中剂量、高剂量组的平均生存时间分别为14、10、5d.不良反应主要表现为炎症反应、肠梗阻、肠道蠕动功能丧失以及死亡.结论 PDT剂量是影响疗效的重要因素,合适剂量的PDT对兔直肠癌有较好的消除效果.对这些问题的深入研究有助于PDT治疗直肠癌的临床应用.     

Correlation of in vivo photosensitizer fluorescence and photodynamic-therapy-induced depth of necrosis in a murine tumor model

We compared light-induced fluorescence (LIF) to nominal injected drug dose for predicting the depth of necrosis response to photodynamic therapy (PDT) in a murine tumor model. Mice were implanted with radiation-induced fibrosarcoma (RIF) and were injected with 0, 5, or 10 mg/kg Photofrin. 630-nm light (30 J/cm(2), 75 mW/cm(2)) was delivered to the tumor after 24 hours. Fluorescence emission (lambda(excitation)=545 nm, lambda( emission)=628 nm) from the tumor was measured. The LIF data had less scatter than injected drug dose, and was found to be at least as good as an injected drug dose for predicting the depth of necrosis after PDT. Our observations provide further evidence that fluorescence spectroscopy can be used to quantify tissue photosensitizer uptake and to predict PDT tissue damage.     

Photodynamic efficacy of photosensitizers under an attenuated light dose via lipid nano-carrier-mediated nuclear targeting

Photodynamic therapy (PDT) has emerged as a treatment for certain malignant-like skin, head and neck, gastrointestinal, and gynecological cancers. The broader acceptance of PDT treatment for large or deep-seated tumors is still hindered, at least in part, by the low photodynamic efficiency of photosensitizers (PS) in the deep-seated tumor environment where the light energy fluency rate is severely attenuated after propagation via skin and/or tissue barriers. In this report, efficient nuclear-targeted intracellular delivery of PS is achieved using an easily fabricated yet entirely biocompatible and inexpensive polysaccharide-functionalized nanoscale lipid carrier, which triggers the intracellular release of photosensitizers inside cancer cells and targets cell nuclear to achieve a significantly enhanced photocytotoxicity. Cancer cells are killed efficiently even under an extremely low light fluency of 1 mW/cm(2) attenuated via an interval meat layer with a thickness of 3 mm. Therefore, this nuclei-targeting system may contribute to the development of a new generation of PS carriers that fight against deep-seated tumors and that exhibit excellent photodynamic efficiency under faint light irradiation.     

Spatial distribution of liposome encapsulated tin etiopurpurin dichloride (SnET2) in the canine prostate: implications for computer simulation of photodynamic therapy

Photodynamic therapy (PDT) is a minimally invasive treatment that can be employed in many human diseases including prostate cancer. PDT for prostate cancer depends on the sequestration of a photosensitizing drug within the glandular tissue. The photosensitizer is subsequently activated by light (usually from a laser) and the active drug destroys tissue. Since prostate cancer is a multifocal disease, PDT must ablate the glandular prostate completely. This will depend on the precise placement of light sources in the prostate and delivery of a therapeutic light dose to the entire gland. Also, sources of light and their spatial distribution must be tailored to each individual patient. The uniform, therapeutic light distribution can be achieved by interstitial light irradiation. In this case, the light is delivered by diffusers placed within the substance of the prostate parallel to the urethra at a distance optimized to deliver adequate levels of light and to create the desired photodynamic effect. To help achieve the uniform light distribution throughout the prostate we have developed a computer program that can determine treatment effects. The program predicts the best set of parameters and the position of light diffusers in space, and displays them in graphical or in numerical form assuming a fixed attenuation coefficient. The two parameters of greatest importance in the computer simulation are attenuation coefficient and critical fluence. Both depend on the concentration of active drug within the prostate gland. It is necessary to know the nature of the spatial distribution of photosensitizer within the prostate to execute computer modeling of PDT with high precision. We found that the concentration of SnET2 is heterogeneous in nature, and is higher in the proximity of the glandular capsule. It is clear therefore that any future attempts of computerized modeling of this procedure must take into consideration the uneven sequestration of photosensitizer and the consequential asymmetrical necrosis of the prostate.     

Potentiation of the photodynamic action of hypericin.

Hypericin (HY) is an interesting photosensitizer with dark activity and photodynamic therapy (PDT) effects via p53-independent pathway. In photodynamic diagnosis (PDD) of bladder cancer using HY, very high sensitivity and specificity were reported, in comparison with its counterpart, 5-aminolevulinic acid (5-ALA). HY was tested for the detection of human gastric cancer. It was also studied for treating some cancers and age-related macular degeneration and showed some promising findings. Several strategies to enhance the efficacy of HY-PDD and HY-PDT are reviewed. Using fractionated light dosing, fractionated drug dosing, hyperthermia, adjuvants such as oxygen carrier/antiangiogenesis, chemical modifications, and formulation approaches to enhance the PDT effects of HY are topics of this review. Despite cutting-edge technology approach such as preparing transferring-mediated targeting HY liposomes and nanoparticles of HY, such preparations did not always offer the desired enhanced treatment effects. It turns out that simple solutions of HY, especially those prepared without using plasma protein, were more successful in enhancing the delivery of HY for in vitro and in vivo systems. Thus, the HY-PDT with these formulations performed better. It is anticipated that HY-PDD and HY-PDT can be enhanced and optimized with the right combination of light dosimetry and drug dose in an effective formulation containing a suitable adjuvant. Hyperoxygenation and hyperthermia can also be used to further enhance the efficacy of HY-PDT.     

研究不同光敏剂诱导的光动力疗法对人白血病细胞的杀伤作用

目的 研究并比较3种卟啉类光敏剂——血卟啉衍生物(HpD)、癌光啉(PsD007)和血卟啉 单甲醚(HMME)诱导的光动力疗法(PDT)对白血病细胞K562的杀伤效应.方法 以人白血病细胞K562为研究对象,分为对照组和PDT组,以梯度浓度的光敏剂与K562细胞共同孵育,经不同能量光照后,用噻唑蓝(MTT)法测定PDT对K562细胞的杀伤作用.结果 与对照组相比,PDT对K562细胞有明显杀伤作用,并随着光敏剂浓度的增加和光照能量的增大,效果增强.PsD007-PDT和HMME-PDT的效果都明显优于HpD-PDT(P＜0.05);而当光敏剂质量浓度较大(25 μg/ml)或能量密度较大(7.2 J/cm2)时,PsD007-PDT的作用效果优于HMME-PDT.结论 PDT对人白血病细胞K562具有明显的杀伤作用,其对细胞的抑制率具有显著的剂量效应关系;PDT对K562的杀伤效应与光敏剂种类有关,HpD-PDT的杀伤效果不如PsD007和HMME;在较高能量密度和较大光敏剂浓度的条件下,PsD007-PDT的效果优于HMME-PDT.     

Updated results of a phase I trial of motexafin lutetium-mediated interstitial photodynamic therapy in patients with locally recurrent prostate cancer.

Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic therapy (PDT), is a modality that uses laser light, drug photosensitizer, and oxygen to kill tumor cells through direct cellular cytotoxicity and/or through destruction of tumor vasculature. A Phase I trial of interstitial PDT with the photosensitizer Motexafin lutetium was initiated in men with locally recurrent prostate cancer. In this ongoing trial, the primary objective is to determine the maximally tolerated dose of Motexafin lutetium-mediated PDT. Other objectives include evaluation of Motexafin lutetium uptake from prostate tissue using a spectrofluorometric assay and evaluation of optical properties in the human prostate. Fifteen men with biopsy-proven locally recurrent prostate cancer and no evidence of distant metastatic disease have been enrolled and 14 have been treated. Treatment plans were developed using transrectal ultrasound images. The PDT dose was escalated by increasing the Motexafin lutetium dose, increasing the 732 ran light dose, and decreasing the drug-light interval. Motexafin lutetium doses ranged from 0.5 to 2 mg/kg administered IV 24, 6, or 3 hr prior to 732 ran light delivery. The light dose, measured in real time with in situ spherical detectors was 25-100 J/cm2. Light was delivered via optical fibers inserted through a transperineal brachytherapy template in the operating room. Optical property measurements were made before and after light therapy. Prostate biopsies were obtained before and after light delivery for spectrofluorometric measurements of photosensitizer uptake. Fourteen patients have completed protocol treatment on eight dose levels without dose-limiting toxicity. Grade I genitourinary symptoms that are PDT related have been observed. One patient had Grade II urinary urgency that was urinary catheter related. No rectal or other gastrointestinal PDT-related tox-icities have been observed to date. Measurements of Motexafin lutetium demonstrated the presence of photosensitizer in prostate tissue from all patients. Optical property measurements demonstrated substantial heterogeneity in the optical properties of the human prostate gland which supports the use of individualized treatment planning for prostate PDT.     

Fluorescence monitoring of a topically applied liposomal Temoporfin formulation and photodynamic therapy of nonpigmented skin malignancies.

Meso-tetra(hydroxyphenyl)chlorin (mTHPC) (INN: Temoporfin) is a potent photodynamically active substance in clinical use today. Usually, the substance is given systemically and a known drawback with this administration route is a prolonged skin light sensitization. For the first time to our knowledge, a liposomal Temoporfin gel formulation for topical application was studied in connection with photodynamic therapy (PDT) of nonpigmented skin malignancies in humans. Intervals of 4 hr between drug administration and light irradiation were used. Sensitizer distribution within tumor and surrounding normal skin was investigated by means of point monitoring and imaging fluorescence spectroscopy before, during, and after PDT, showing high tumor selectivity. Furthermore, the bleaching of Temoporfin was studied during the PDT procedure by monitoring the fluorescence following excitation by using a therapeutic light. A 30-35% light-induced photometabolization was shown. No pain occurred during or after treatment. It was also observed that the treated area did not show any swollen tissue or reddening, as is often seen in PDT using topical delta-aminolevulinic acid. On controlling the patients one week after treatment, healing progress was observed in several patients and no complications were registered.