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.

The three-dimensional (3D) heterogeneous distributions of optical properties in a patient prostate can now be measured in vivo. Such data can be used to obtain a more accurate light-fluence kernel. (For specified sources and points, the kernel gives the fluence delivered to a point by a source of unit strength.) In turn, the kernel can be used to solve the inverse problem that determines the source strengths needed to deliver a prescribed photodynamic therapy (PDT) dose (or light-fluence) distribution within the prostate (assuming uniform drug concentration). We have developed and tested computational procedures to use the new heterogeneous data to optimize delivered light-fluence. New problems arise, however, in quickly obtaining an accurate kernel following the insertion of interstitial light sources and data acquisition. (1) The light-fluence kernel must be calculated in 3D and separately for each light source, which increases kernel size. (2) An accurate kernel for light scattering in a heterogeneous medium requires ray tracing and volume partitioning, thus significant calculation time. To address these problems, two different kernels were examined and compared for speed of creation and accuracy of dose. Kernels derived more quickly involve simpler algorithms. Our goal is to achieve optimal dose planning with patient-specific heterogeneous optical data applied through accurate kernels, all within clinical times. The optimization process is restricted to accepting the given (interstitially inserted) sources, and determining the best source strengths with which to obtain a prescribed dose. The Cimmino feasibility algorithm is used for this purpose. The dose distribution and source weights obtained for each kernel are analyzed. In clinical use, optimization will also be performed prior to source insertion to obtain initial source positions, source lengths and source weights, but with the assumption of homogeneous optical properties. For this reason, we compare the results from heterogeneous optical data with those obtained from average homogeneous optical properties. The optimized treatment plans are also compared with the reference clinical plan, defined as the plan with sources of equal strength, distributed regularly in space, which delivers a mean value of prescribed fluence at detector locations within the treatment region. The study suggests that comprehensive optimization of source parameters (i.e. strengths, lengths and locations) is feasible, thus allowing acceptable dose coverage in a heterogeneous prostate PDT within the time constraints of the PDT procedure.

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Optimization of light source parameters in the photodynamic therapy of heterogeneous prostate

Our objective in this study has been to investigate how head scatter varies with the off-axis position in a 6 MV x-ray beam. We define the head-scatter off-axis ratio, HOA, as the ratio of the kerma due to head-scatter photons at the off-axis position x to the kerma from direct primary photons on the central axis. "Direct primary" are those photons that come from the source without interactions in the intervening structures. We determined HOA from measurements with an ionization chamber in a miniphantom. Head-scatter and direct primary photons contribute to a measurement of the ionization per mu Q(x) at the off-axis position x in the open field cx x cy. The ionization per mu QP(x), measured in the same position but with the field collimated to the smallest possible opening (cx x 3 cm), is intended to include only direct primary photons. Head-scatter photons cannot be completely eliminated, and the errors due to remaining head scatter and radiation back-scattered by the movable collimators into the monitor were estimated. For normalization of the final results, ionization due to direct primary photons was also measured on the central axis, QP(0). HOA was derived from these three measurements as HOA(cx,cy,x)=(Q(cx,cy,x) - QP(cx,cy,x))/QP(cx,cy,0). On the central axis (x=y=0), HOA represents the "scatter-to-primary ratio" between head scatter and the direct primary dose. Monte Carlo simulations were made to help with the interpretation and evaluation of the results. HOA could be fitted to a Gaussian model with two components corresponding to sources of widths 1.8 and 14 cm, projected on a plane 5 cm below the x-ray source. The narrow Gaussian component is interpreted as the source of photons scattered in the flattening filter and the primary collimator. The broad component is attributed to photons scattered in the secondary (variable) collimators. Conventional head-scatter models (e.g., a single Gaussian source model) do not fit the measured HOA data for large collimator settings (c>20 cm) or outside beam collimation. The full width at half-maximum (FWHM) of HOA(x) across the field increased with the field width (cx) in the direction of the measurements in a manner consistent with the field of view of the two sources. It was not sensitive to the field measure in the orthogonal direction (cy). Head scatter outside the field also increased with field size, reflecting an increased contribution of photons scattered at large angles. It exceeds the leakage through the collimator 2 cm outside the edge for square fields c>10 cm. Monte Carlo calculations showed considerably less head scatter outside the field than measurements.

Head scatter off-axis for megavoltage x rays.

Tail latency is of great importance in user-facing web services. However, maintaining low tail latency is challenging, because a single request to a web application server results in multiple queries to complex, diverse backend services (databases, recommender systems, ad systems, etc.). A request is not complete until all of its queries have completed. We analyze a Microsoft production system and find that backend query latencies vary by more than two orders of magnitude across backends and over time, resulting in high request tail latencies.We propose a novel solution for maintaining low request tail latency: repurpose existing caches to mitigate the effects of backend latency variability, rather than just caching popular data. Our solution, RobinHood, dynamically reallocates cache resources from the cache-rich (backends which don't affect request tail latency) to the cache-poor (backends which affect request tail latency). We evaluate RobinHood with production traces on a 50- server cluster with 20 different backend systems. Surprisingly, we find that RobinHood can directly address tail latency even if working sets are much larger than the cache size. In the presence of load spikes, RobinHood meets a 150ms P99 goal 99.7% of the time, whereas the next best policy meets this goal only 70% of the time.

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RobinHood: tail latency-aware caching—dynamically reallocating from cache-rich to cache-poor

Photodynamic therapy (PDT) is known as a non-invasive treatment modality that is based on photochemical reactions between oxygen, photosensitizer, and a special wavelength of light. However, a dosimetric predictor for PDT outcome is still elusive because current dosimetric quantities do not account for the differences in the PDT oxygen consumption rate for different fluence rates. In this study, we evaluate several dose metrics, total fluence, photobleaching ratio, PDT dose, and mean reacted singlet oxygen (mean [1 O2 ]rx ) for predicting the PDT outcome and a clinically relevant tumor re-growth endpoint. For this reason, radiation-induced fibrosarcoma (RIF) mice tumors are treated with 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) and different in-air fluences (30 J/cm2 , 50 J/cm2 , 135 J/cm2 , 250 J/cm2 , and 350 J/cm2 ) and in-air fluence rates (20, 50, 75, 150 mW/cm2 ). Explicit measurements of HPPH and oxygen concentration as well as tissue optical properties are performed pre- and post-treatment. Then, this information is incorporated into a macroscopic model to calculate the photobleaching, PDT dose, and mean [1 O2 ]rx . Changes in tumor volume are tracked following the treatment and compared with the dose metrics. The correlation demonstrates that mean [1 O2 ]rx  serves as a better dosimetric quantity for predicting treatment outcome and a clinically relevant tumor re-growth endpoint.

Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling.

Therapeutic options for patients with locally recurrent prostate cancer after treatment with radiation therapy are limited. An ongoing Phase I trial of interstitial photodynamic therapy (PDT) with the photosensitizer motexafin lutetium (MLu) was initiated in year 2000 for men with locally recurrent prostate cancer. The primary objective of this trial is to determine the maximally tolerated dose of motexafin lutetium-mediated PDT. Twelve men with biopsy-proven recurrent prostate cancer and no evidence of distant metastatic disease have been enrolled. Pre-treatment evaluation included an MRI of the prostate, bone scan, laboratory studies, cystoscopy, and transrectal ultrasound. Treatment plans were generated based upon the ultrasound findings. PDT dose was escalated by increasing the motexafin lutetium dose, increasing the 732 nm light dose, and decreasing the drug-light interval. Motexafin lutetium doses ranged from 0.5 to 2 mg/kg administered IV 3, 6, or 24 hours prior to 732 nm light delivery. The light dose measured in real time with in situ spherical detectors was 25-100 J/cm2 for all patients. Light was delivered through optical fibers inserted through a transperineal brachytherapy template in the operating room and 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. Twelve patients have completed protocol treatment on eight dose levels without dose-limiting toxicity. Grade I PDT-related genitourinary symptoms were observed. One patient had Grade II urinary urgency that was urinary catheter-related. No rectal or other GI PDT-related toxicities were observed. Measurements of motexafin lutetium in prostate tissue demonstrated the presence of photosensitizer at all dose levels. Conclusions: Motexafin lutetium-mediated PDT designed to treat comprehensively the entired prostate gland has been well-tolerated at the doses studied to date.

Timothy C. Zhu

Papers

Optimization of light source parameters in the photodynamic therapy of heterogeneous prostate

Head scatter off-axis for megavoltage x rays.

RobinHood: tail latency-aware caching—dynamically reallocating from cache-rich to cache-poor

Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling.

Phase I trial of motexafin-lutetium-mediated interstitial photodynamic therapy in patients with locally recurrent prostate cancer