The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

Photodynamic therapy for cancer

CA : A Cancer Journal for Clinicians

NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

sources and effects of ionizing radiation

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

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Photodynamic therapy of cancer: An update†‡

A review of reported tissue optical properties summarizes the wavelength-dependent behavior of scattering and absorption. Formulae are presented for generating the optical properties of a generic tissue with variable amounts of absorbing chromophores (blood, water, melanin, fat, yellow pigments) and a variable balance between small-scale scatterers and large-scale scatterers in the ultrastructures of cells and tissues.

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Optical properties of biological tissues: a review.

Mathematic models were developed to simulate the complex dynamic process of photodynamic therapy (PDT). Macroscopic or microscopic modeling of singlet oxygen ( 1 O 2 ) is particularly of interest because it is the major cytotoxic agent causing biological effects during PDT. Our previously introduced macroscopic PDT model incorporates the diffusion equation for the light propagation in tissue and the macroscopic kinetic equations for the production of the 1 O 2 . The distance-dependent distribution of 3 O 2 and reacted 1 O 2 can be numerically calculated using finite-element method (FEM). We recently improved the model to include microscopic kinetic equations of oxygen diffusion from uniformly distributed blood vessels and within tissue. In the model, the cylindrical blood capillary has radius in the range of 2-5 μm and a mean length of 300 μm, and supplies oxygen into tissue. The blood vessel network is assumed to form a 2-D square grid perpendicular to a linear light source. The spacing of the grid is 60 μm. Oxygen can also diffuse along the radius and the longitudinal axial of the cylinder within tissue. The oxygen depletion during Photofrin-PDT PDT can be simulated using both macroscopic and microscopic approaches. The comparison of the simulation results have reasonable agreements when velocity of blood flow is reduced during PDT.

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A theoretical comparison of macroscopic and microscopic modeling of singlet oxygen during Photofrin and HPPH mediated-PDT

Type II photodynamic therapy (PDT) is based on the use of photochemical reactions mediated through an interaction
between a tumor-selective photosensitizer, photoexcitation with a specific wavelength of light, and production of
reactive singlet oxygen. However, the medical application of this technique has been limited due to inaccurate PDT
dosimetric methods. The goal of this study is to examine the relationship between outcome (in terms of tumor growth
rate) and calculated reacted singlet oxygen concentration [1O2]rx after HPPH-mediated PDT to compare with other PDT
dose metrics, such as PDT dose or total light fluence. Mice with radiation-induced fibrosarcoma (RIF) tumors were
treated with different light fluence and fluence rate conditions. Explicit measurements of photosensitizer drug
concentration and tissue optical properties via fluorescence and absorption measurement with a contact probe before and
after PDT were taken to then quantify total light fluence, PDT dose, and [1O2]rx based on a macroscopic model of singlet
oxygen. In addition, photobleaching of photosenitizer were measured during PDT as a second check of the model.
Changes in tumor volume were tracked following treatment and compared to the three calculated dose metrics. The
correlations between total light fluence, PDT dose, reacted [1O2]rx and tumor growth demonstrate that [1O2]rx serves as a
better dosimetric quantity for predicting treatment outcome and a clinically relevant tumor growth endpoint.

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In-vivo outcome study of HPPH mediated PDT using singlet oxygen explicit dosimetry (SOED)

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

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Light Dosimetry at Tissue Surfaces for Oblique Incident Circular Fields.

Purpose: To characterize basic performance of plastic scintillator detectors (PSD) designed for dosimetry of radiation therapy. Methods: The Exradin W1 Scintillator is a plastic scintillating fiber-based detector designed for highly accurate measurement of small radiotherapy fields used in patient plan verification and machine commissioning and QA procedures. The Cerenkov emissions were corrected using spectral separation. The optical signal was converted to electronic signal with a photodiode. We measured its dosimetry performance, including percentage depth dose, output factor, dose and dose rate linear response. We compared the dosimetry results with reference ion chamber measurements. Results: The dosimetry results of PSD agree well with reference ion chamber measurements. For percentage depth dose, the differences between PSD and ion chamber results are on average 1.7±1.1% and 0.8±0.8% with a maximum of 3.5% and 2.7% for 6MV and 15MV beams, respectively. For the output factors, PSD measurements are within 2% from ion chamber results. The dose linear response is within 1% when dose is larger than 20 MU for both 6 MV and 15 MV. The dose rate linear response is within 1% for the entire dose rate used (100 MU/min to 600MU/min). Conclusions: The current design of PSD is feasible for the dosimtry measurement in radiation therapy. This combination of PSD and photodiode system could be extended to multichannel array detection of dose distribution. It might as well be used as range verification in proton therapy. The work is partially supported by: DOD (W81XWH-09-2-0174) and American Cancer Society (IRG-78-002-28)

SU-E-T-553: Characterization of Plastic Scintillator Detectors for Radiation Therapy

Accurate determination of in-vivo light fluence rate is critical for preclinical and clinical studies involving photodynamic therapy (PDT). This study compares the longitudinal light fluence distribution inside biological tissue in the central axis of a 1 cm diameter circular uniform light field for a range of in-vivo tissue optical properties (absorption coefficients ( P a ) between 0.01 and 1 cm -1 and reduced scattering coefficients ( P s ) between 2 and 40 cm -1 ). This was done using Monte-Carlo simulations for a semi -infinite turbid medium in an air-tissue interface. The end goal is to develop an analytical expression that would fit the results from the Monte Carlo simulation for both the 1 cm diameter circular beam and the broad beam. Each of these parameters is expressed as a function of tissue optical properties. These results can then be compared against the existing expressions in the literature for broad beam for analysis in both accuracy and applicable range. Using the 6-parameter model, the range and accuracy for light transport through biological tissue is improved and may be used in the future as a guide in PDT for light fluence distribution for known tissue optical properties. Keywords: MC, PDT, semi-infinite medium, analytical expression

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Timothy C. Zhu

Papers

A theoretical comparison of macroscopic and microscopic modeling of singlet oxygen during Photofrin and HPPH mediated-PDT

In-vivo outcome study of HPPH mediated PDT using singlet oxygen explicit dosimetry (SOED)

Light Dosimetry at Tissue Surfaces for Oblique Incident Circular Fields.

SU-E-T-553: Characterization of Plastic Scintillator Detectors for Radiation Therapy

An improved analytic function for predicting light fluence rate in circular fields on a semi-infinite geometry