Photodynamic therapy: mechanism of action and role in the treatment of skin disease.

The combination of lesion ablation with excellence in cosmetic outcome has allowed photodynamic therapy (PDT) an ever increasing role in the treatment of diseases of the skin. As currently practiced, PDT employs a photosensitizing agent that when activated by light energy creates a photodynamic reaction that is cytotoxic and vasculotoxic. The relative simplicity of therapy with its ability to achieve high response rates has brought PDT to a worldwide audience not only for oncologic indications but far more commonly to non oncologic indications. This paper will review the mechanism of action for PDT and highlight the versatile clinical outcomes reported from the peer reviewed literature.

Determination of absorbed dose in water at the reference point d(r0, theta0) for an 192Ir HDR brachytherapy source using a Fricke system.

A ring-shaped Fricke device was developed to measure the absolute dose on the transverse bisector of a 192Ir high dose rate (HDR) source at 1 cm from its center in water, D(r0, theta0). It consists of a polymethylmethacrylate (PMMA) rod (axial axis) with a cylindrical cavity at its center to insert the 192Ir radioactive source. A ring cavity around the source with 1.5 mm thickness and 5 mm height is centered at 1 cm from the central axis of the source. This ring cavity is etched in a disk shaped base with 2.65 cm diameter and 0.90 cm thickness. The cavity has a wall around it 0.25 cm thick. This ring is filled with Fricke solution, sealed, and the whole assembly is immersed in water during irradiations. The device takes advantage of the cylindrical geometry to measure D(r0, theta0). Irradiations were performed with a Nucletron microselectron HDR unit loaded with an 192Ir Alpha Omega radioactive source. A Spectronic 1001 spectrophotometer was used to measure the optical absorbance using a 1 mL quartz cuvette with 1.00 cm light pathlength. The PENELOPE Monte Carlo code (MC) was utilized to simulate the Fricke device and the 192Ir Alpha Omega source in detail to calculate the perturbation introduced by the PMMA material. A NIST traceable calibrated well type ionization chamber was used to determine the air-kerma strength, and a published dose-rate constant was used to determine the dose rate at the reference point. The time to deliver 30.00 Gy to the reference point was calculated. This absorbed dose was then compared to the absorbed dose measured by the Fricke solution. Based on MC simulation, the PMMA of the Fricke device increases the D(r0, theta0) by 2.0%. Applying the corresponding correction factor, the D(r0, theta0) value assessed with the Fricke device agrees within 2.0% with the expected value with a total combined uncertainty of 3.43% (k=1). The Fricke device provides a promising method towards calibration of brachytherapy radiation sources in terms of D(r0, theta0) and audit HDR source calibrations.

Toward endobronchial Ir-192 high-dose-rate brachytherapy therapeutic optimization.

A number of patients with lung cancer receive either palliative or curative high-dose-rate (HDR) endobronchial brachytherapy. Up to a third of patients treated with endobronchial HDR die from hemoptysis. Rather than accept hemoptysis as an expected potential consequence of HDR, we have calculated the radial dose distribution for an Ir-192 HDR source, rigorously examined the dose and prescription points recommended by the American Brachytherapy Society (ABS), and performed a radiobiological-based analysis. The radial dose rate of a commercially available Ir-192 source was calculated with a Monte Carlo simulation. Based on the linear quadratic model, the estimated palliative, curative and blood vessel rupture radii from the center of an Ir-192 source were obtained for the ABS recommendations and a series of customized HDR prescriptions. The estimated radius at risk for blood vessel perforation for the ABS recommendations ranges from 7 to 9 mm. An optimized prescription may in some situations reduce this radius to 4 mm. The estimated blood perforation radius is generally smaller than the palliative radius. Optimized and individualized endobronchial HDR prescriptions are currently feasible based on our current understanding of tumor and normal tissue radiobiology. Individualized prescriptions could minimize complications such as fatal hemoptysis without sacrificing efficacy. Fiducial stents, HDR catheter centering or spacers and the use of CT imaging to better assess the relationship between the catheter and blood vessels promise to be useful strategies for increasing the therapeutic index of this treatment modality. Prospective trials employing treatment optimization algorithms are needed.

PDT experience in Brazil: A regional profile.

The success of PDT and its establishment into the existent hall of therapeutic modalities depends on the collection of reported experiences from around the world. In that sense, it is important to report approaches taken by different countries and what their views are on the future of PDT. Following this idea, we present our clinical experience in photodynamic therapy (PDT) in Brazil, as well as the experimental advances coming up in parallel with clinical implementation. This report is a consequence of pioneering work in a collaborative program involving the Physics Institute in São Carlos, São Paulo State (SP), Brazil, the Medical School of the University of São Paulo, Ribeirão Preto, SP, Brazil and the Cancer Hospital Amaral Carvalho, Jaú, SP, Brazil. This collaborative program, begun in 1997, with the first patient treated in 1999, has treated over 400 patients by late 2004. About 80% of lesions were located in the head and neck or skin, but experience is being built in esophagus, bladder, gynecology, and cutaneous recurrence of breast cancer, among others. The overall results have shown to be compatible with previously reported data. Modifications, whose goal is to improve patient benefit and optimize results, are being implemented as we gain experience. In parallel with the clinical development, several laboratories have started studying experimental whose purpose is to analyze the clinical results and to contribute to the worldwide effort to bring PDT to the forefront of therapies offered to patients. We present the overall results of our 5 years experience as well as the whole implementation process.

Clinical photodynamic therapy of head and neck cancers-A review of applications and outcomes.

As local control is tantamount to cure in head and neck cancer, an aggressive regimen of surgery and radiation remains the standard of care for most patients. Despite significant technical advances, these treatments are highly morbid. Further, patients who fail treatment have limited salvage options. Photodynamic therapy (PDT) and photodiagnosis (PD) of head and neck cancer offer significant potential for improved outcomes in a myriad of clinical indications ranging from in situ to recurrent disease. However, despite promising results, these modalities remain at the fringe of head and neck treatment options. Photofrin(®), Photosan and Foscan(®) are photosensitizers used clinically in head and neck PD/PDT. In addition, aminolevulinic acid (ALA), which gives origin to Protoporphyrin IX, an endogeneous photosensitizer, is also used for PD/PDT. We review the clinical literature on these photosensitizers to assist in the integration of these important modalities into the mainstream of head and neck oncological therapy.

PD/PDT for gynecological disease: A clinical review.

The evolution of diagnostic and interventional procedures for gynecologic disease has led to organ, sexual and reproductive sparing treatments. Photodiagnosis (PD) and photodynamic therapy (PDT) may play a great role for gynecological patients as both offer the potential to achieve these goals. PD/PDT for a wide variety of diagnostic and therapeutic interventions have shown potential for excellent clinical outcomes. However, significant limitations remains, both clinically and dosimetrically, that prevent consistent results. When those limitations are resolved PD/PDT could move to the forefront of gynecological therapy. This clinical review highlights the outcomes and shortcomings of PD/PDT through the peer reviewed literature for gynecological sites.

Influence of hip prostheses on high energy photon dose distributions.

Radiotherapy treatment of patients having a hip prosthesis is a common problem facing dosimetrists and physicists when the treatment plan requires irradiation of the pelvic area. To quantify the perturbation of these devices, attenuation studies were done with 6 and 18 MV photon beams using various hip prostheses models with varying size and composition. These studies have shown that an attenuation of as much as 50% can be found in a single beam profile under the prosthesis. We have studied the capability of a dose planning system to predict the transmission of these devices as compared with measurements.

Build-up curves of scanned high energy electron beams from the Sagittaire linear accelerator.

A study of the build-up curves using an extrapolation chamber for 7, 10, 13, 16, and 19 MeV electron beams, from a Sagittaire linear accelerator, is presented. The effect of the ionization chamber bias polarity, field size, collimation and surface obliquity on the shape of the relative ionization curve was investigated. No clinically significant change is observed except the displacement of the maximum ionization point was observed for the oblique incidence of the beam.

Deconvolution of detector size effect for small field measurement.

Parametrization of the small fields employed in stereotactic applications is a painstaking process involving extensive film dosimetry to achieve acceptable beam edge definition. Use of cylindrical or spherical detectors for profile measurements would simplify data acquisition but add a volume averaging artifact to beam edge definition. We demonstrate a simple approach to unfolding the chamber size artifact from measured small beam profiles using typical cylindrical chambers. In comparison with film measurements we have found good agreement when the detector response function is deconvoluted from the measured profiles, although the amount of correction needed is fairly minimal for the detectors studied.

A graphite transmission ionization chamber.

A pancake-type transmission chamber made of high-purity graphite and open to the atmosphere has been designed and constructed at the Secondary Standard Dosimetry Laboratory (SSDL-Rio de Janeiro). Tests performed on the chamber following the International Electrotechnical Commission recommendations indicate that its performance characteristics are comparable to those expected from a secondary standard ionization chamber.

Scatter factor corrections for elongated fields.

Measurements have been made to determine scatter factor corrections for elongated fields of Cobalt-60 and for nominal linear accelerator energies of 6 MV (Siemens Mevatron 67) and 18 MV (AECL Therac 20). It was found that for every energy the collimator scatter factor varies by 2% or more as the field length-to-width ratio increases beyond 3:1. The phantom scatter factor is independent of which collimator pair is elongated at these energies. For 18 MV photons it was found that the collimator scatter factor is complicated by field-size-dependent backscatter into the beam monitor.

Calculational methods for estimating skin dose from electrons in Co-60 gamma-ray beams.

Several methods have been employed to calculate the relative contribution to skin dose due to scattered electrons in Co-60 gamma-ray beams. Either the Klein-Nishina differential scattering probability is employed to determine the number and initial energy of electrons scattered into the direction of a detector, or a Gaussian approximation is used to specify the surface distribution of initial pencil electron beams created by parallel or diverging photon fields. Results of these calculations are compared with experimental data. In addition, that fraction of relative surface dose resulting from photon interactions in air alone is estimated and compared with data extrapolated from measurements at large source-surface distance (SSD). The contribution to surface dose from electrons generated in air is 50% or more of the total skin dose for SSDs greater than 80 cm.

Experimental derivation of wall correction factors for ionization chambers used in high dose rate 192Ir source calibration.

At present there are no specific primary standards for 192Ir high dose rate sources used in brachytherapy. Traceability to primary standards is guaranteed through the method recommended by the AAPM that derives the air kerma calibration factor for the 192Ir gamma rays as the average of the air kerma calibration factors for x-rays and 137Cs gamma-rays or the Maréchal et al. method that uses the energy-weighted air kerma calibration factors for 250 kV x rays and 60Co gamma rays as the air kerma calibration factor for the 192Ir gamma rays. In order to use these methods, it is necessary to use the same buildup cap for all energies and the appropriate wall correction factor for each chamber. This work describes experimental work used to derive the A(W) for four different ionization chambers and different buildup cap materials for the three energies involved in the Maréchal et al. method. The A(W) for the two most common ionization chambers used in hospitals, the Farmer NE 2571 and PTW N30001 is 0.995 and 0.997, respectively, for 250 kV x rays, 0.982 and 0.985 for 192Ir gamma rays, and 0.979 and 0.991 for 60Co gamma rays, all for a PMMA build-up cap of 0.550 gm cm(-2). A comparison between the experimental values and Monte Carlo calculations shows an agreement better than 0.9%. Availability of the A(W) correction factors for all commercial chambers allows users of the in-air calibration jig, provided by the manufacturer, to alternatively use the Maréchal et al. method. Calibration laboratories may also used this method for calibration of a well-type ionization chamber with a comparable accuracy to the AAPM method.

Application of thermal dilution measurements for thermal treatment planning.

The use of thermal dilution measurements is demonstrated in quantifying effective thermal conductivity distributions through tumours. For focused acoustic sources these data are applied in the solution of the heat diffusion equation to estimate steady-state temperature distributions. The advantages and disadvantages of this approach are presented. The effective conductivity measurements are found to be useful in predicting the circumstances under which this simple model can be applied and in aiding the selection of the most appropriate heating modality.

Determination of contamination-free build-up for 60Co.

Experimental verification of the difference between absorbed dose in tissue and the collision fraction of kerma requires precise knowledge of the absorbed dose curve, particularly in the build-up and build-down regions. A simple method for direct measurement of contamination-free build-up for 60Co, which should also be applicable for most of the photon energies commonly employed for treatment, is presented. It is shown that the contribution from air-scattered electrons to the surface dose may be removed by extrapolating measurements of build-up to zero field size. The remaining contribution to contamination from the collimators and other source-related hardware may be minimised by measuring these build-up curves sufficiently far from the source. These results were tested by measuring the build-up using a magnet to sweep scattered electrons from the primary photon beam and by measuring the surface dose in the limit of an evacuated beam path. The relative dose at zero depth in polystyrene was found to be approximately 8.9 +/- 0.3% of the dose at the depth of maximum build-up.

Influence of detector size in photon beam profile measurements.

Correction is necessary to account for the detector size in clinical dosimetry of photon and electron beams. This correction is due to the absorbed dose gradient present in a finite-size detector. Further corrections are necessary when the detector and phantom materials are not the same. These corrections are due to the perturbation in the charged-particle fluence. Generally these corrections are applied to measurements along the central axis of the beam. Cross beam profile measurements, however, are not usually corrected for detector size. The ionization profile is also usually assumed to be equivalent to the absorbed dose profile. We have corrected the ionization chamber size effect by two approaches: extrapolation of measurements to zero detector size and deconvolution of measurements using a simple model for the detector response function. We have measured absorbed dose profiles to water using a small water-equivalent plastic scintillation detector. Film profile measurements were also studied. The ionization profile corrected for detector size and absorbed dose profile were not equal, probably due to loss of charged-particle equilibrium in the beam edges. For ionization chamber measurements, knowledge of the charged-particle spectrum is needed to convert ionization to absorbed dose to water. This is not necessary for relative absorbed dose measurements under charged-particle equilibrium. Film has been shown to be a straightforward and reliable method for cross beam profile measurements.

The use of customized spreadsheets in radiation therapy.

A number of radiation-therapy-related uses based on a commercially available spreadsheet program have been developed at our facility. The graphics and display capabilities inherent in these spreadsheet programs allow for concise visual results. The spreadsheets are used as an independent check for several types of radiation therapy dose calculations. External beam--a spreadsheet will verify the monitor units (MU) or time required to deliver a prescribed dose to a point on an isodose line as calculated by a commercial treatment planning system. Calibration--spreadsheet programs have been developed to perform the calculations necessary for the output calibration of cobalt and high-energy photon and electron beams according to the TG-21 protocol. The user must indicate which beam, electrometer, chamber, phantom material, temperature, pressure and depth of measurement that apply. Radiosurgery--the MU per arc is calculated based on the following: the average depth per arc as obtained from a commercial radiosurgery program, the collimator size, and the prescription dose. TBI--The patient's width is entered into the spreadsheet program, which then calculates the MU needed to deliver a prescribed dose to the midline.

A well-type ionization chamber geometric correction factor.

To correct for the influence of source configuration on the measured activity of spherical and cylindrical brachytherapy sources, a geometric correction factor was calculated for the Standard Imaging HDR-1000 well-type ionization chamber. A Fortran program modelled each source as a lattice of point sources. Because of the cylindrical symmetry of the well chamber, it could be uniquely modelled by point detectors along the perimeter of the radial plane of the detection volume. Path lengths were calculated and attenuation factors were applied to each source-detector point combination individually. The total dose rate at each detection point was found through a Sievert summation of the point source contributions. For 137Cs sources with identical activities, a correction factor of 0.965 +/- 0.005 was calculated, equal to the ratio of the dose rate of the cylindrical source to that of the sphere. Experimental verification using a Nuclear Associates 67-809 series cylindrical sources and an Amersham spherical 137Cs source yielded a correction factor of 0.958 +/- 0.016.

Uncertainty in delivered dose resulting from the distribution of source activities in a Selectron LDR afterloader.

The uncertainty in the delivered dose resulting from the distribution of 137Cs source activity in a clinical Selectron LDR unit has been studied. A comparison is made of the dose delivered to a point 'A' in an implant with sources of equal activity to the actual dose delivered in the same implant with source activities randomly chosen from the population in the afterloader.

Photodynamic therapy in oncology.

Photodynamic therapy (PDT) is a cancer treatment modality that is based on the administration of a photosensitiser, which is retained in tumour tissues more than in normal tissues, followed by illumination of the tumour with visible light in a wavelength range matching the absorption spectrum of the photosensitiser. The photosensitiser absorbs light energy and induces the production of reactive oxygen species in the tumour environment, generating a cascade of events that kills the tumour cells. The first generation photosensitiser, Photofrin (porfirmer sodium), has been approved for oesophageal and lung cancer in the US and has been under investigation for other malignant and non-malignant diseases. Sub-optimal light penetration at the treatment absorption peak of Photofrin and prolonged skin photosensitivity in patients are limiting factors for this preparation. Several new photosensitisers have improved properties, especially absorption of longer wavelength light which penetrates deeper into tissue and faster clearance from normal tissue. This paper reviews the current use of first- and second-generation photosensitisers in oncology. The use of PDT in oncology has been restricted to certain cancer indications and has not yet become an integral part of cancer treatment in general. The main advantage of PDT is that the treatment can be repeated multiple times safely, without producing immunosuppressive and myelosuppressive effects and can be administered even after surgery, chemotherapy or radiotherapy. The current work on new photosensitisers and light delivery equipment will address some of the present shortcomings of PDT. Much has been learned in recent years about the mechanisms of cellular and tissue responses to PDT and protocols designed to capitalise on this knowledge showed lead to additional improvements.