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• W2018234088 abstract "Arguing against the Proposition is E. Ishmael Parsai, Ph.D. Dr. Parsai was awarded his M.S. and Ph.D. degrees in Medical Physics by the University of Missouri, Columbia in 1988 and the University of Toledo, Ohio in 1995, respectively. Since 1993 he has worked in the Department of Radiation Oncology, University of Toledo, where he is currently Chief of the Medical Physics Division and Professor and Director of Medical Physics Programs in the College of Medicine. His research interests include mathematical modeling using Monte Carlo simulation, optimization of external beam therapy and brachytherapy, 3-D dosimetry, and radiation detectors and he has published 40 peer-reviewed articles and 6 book chapters. Dr. Parsai is certified in radiation therapy physics by both the ABR and the ABMP. PDT is an emerging cancer treatment modality based on the interaction of light, a photosensitizer, and oxygen.1 The mechanism of action involves the production of reactive oxygen species (e.g., singlet oxygen from the oxygen molecule) when a photosensitizer is activated by nonionizing light. The clinical effect caused by the reactive oxygen species can be direct target (tumor) cell kill by necrosis or apoptosis, vascular damage leading to tissue ischemia, immune modulation, or a combination of the three.2 Clinically, PDT has shown some efficacy in the treatment of a variety of malignant and premalignant conditions including head and neck cancer, lung cancer, mesothelioma, Barrett's esophagus, prostate, brain tumors, and skin cancers.3 From a physics point of view, PDT is well suited for skin cancer treatment because of the easy access of disease sites, simple geometry for light delivery, and limited light penetration in tissue. PDT has shown high efficacy for skin cancers, especially for basal cell carcinoma, which is the most common skin cancer in humans.2 Compared to radiation therapy, the major advantages of PDT are threefold. First, nonionizing light is used for tumor killing, thus avoiding targeting DNA and allows PDT to be performed repetitively. Second, photosensitizers may be administered in ways that target tumor and avoid healthy tissues. One common example is ALA which can be applied topically on the region of treatment. Unlike traditional photosensitizers, ALA is a prodrug that can produce a photosensitizer (PpIX) in situ once absorbed by tissue and it has exhibited preferential uptake in tumor cells.4 The third advantage is that the PDT dose response, unlike radiation therapy, usually has a threshold behavior, with a sharp boundary between necrotic and undamaged tissue.2 This can be used to achieve dramatic clinical responses with minimal side effects to adjacent critical organs. PDT has its limitations, mostly due to the complex interactions of light, photosensitizer, and oxygen. Unlike radiation therapy, where the radiation dose is well understood and can be calculated with great accuracy based on CT data, comprehensive in vivo PDT dosimetry, whether implicit or explicit as proposed by Wilson et al.,5 is still emerging and is not used routinely in many clinical trials.2 Accurate PDT dosimetry is essential in order to utilize the full potential of PDT. For some skin cancers such as melanoma, for which PDT treatments are often avoided in the clinic due to perceived limitation of light penetration in melanin,3 comprehensive PDT dosimetry should help optimize new PDT treatment protocols with suitable photosensitizer and light fractionation combinations. In conclusion, despite its many limitations, PDT is much less expensive to use than radiation therapy and has been shown to be highly efficient and noninvasive, with excellent cosmetic results and quicker recovery time after treatment.4 It can often be applied concurrently with radiation therapy and is thus a worthwhile treatment modality to explore further. Radiation therapy (RT) is often indicated as a definitive or adjuvant treatment for skin cancers in patients where the cosmetic and/or functional outcome of a surgical procedure is expected to be unsatisfactory. The main RT modalities for these cases are 50–250 kV superficial x-ray beams, megavoltage electrons and, in more recent years, high dose-rate brachytherapy. The choice of a specific modality is typically made based on the treatment site, the size and location of the lesion, the stage of a disease, and the overall health of the patient. For adjuvant RT, the objective is to reduce the risk of loco-regional recurrence by irradiating the tumor bed after surgery. Brachytherapy offers the advantage of the source of radiation being placed in the immediate proximity to the targeted tumor tissue using surface plaques/molds or intracavitary, interstitial, or intraluminal catheters.6,7 The development of artificial radionuclides and remote afterloading devices has made this procedure safe for both the patient and the delivering personnel. In external beam therapies, megavoltage electrons are gradually replacing superficial x rays in treatment of skin cancers. Use of electron beams is deemed advantageous due to their exceptional dose uniformity within the targeted tissue and a sharp fall-off beyond the distal boundary of tumor. By design, all these procedures allow for the delivery of conformal high total dose to the tumor and minimal dose to the normal surrounding tissues. Radiation dosimetry formalism has been extensively developed and refined into AAPM Task Group reports,8,9 guiding the administration and quality assurance procedures for each modality. Consequently, accurate quantification of prescribed doses to tissues and their safe delivery, as well as the availability of computerized treatment planning systems, have made radiotherapy treatments effective and reliable. Application of photodynamic therapy as an alternative to radiation for skin tumors is still at its infancy. From the patient's side, it is typically a painful procedure10 leading to prolonged phototoxicity.11 From the treatment delivery standpoint, the need to have a combination of conditions (drug, oxygen, and light) to be present for a sufficient biological effect makes this therapy failure-prone and highly patient-dependent. Presently, the practical objective for treatment delivery is to achieve some threshold values12 based on best-known parameters, which are often measured at the time of treatment. The importance of proper dosimetry for the drug uptake, delivered light, and the level of oxygen present in a tissue during the treatment cannot be overemphasized. All three parameters generally have to be evaluated on a patient-by-patient basis, with adjustments made for heterogeneity of the physical and chemical environment. Determination of availability of the level in tissue is sketchy at best13 and the depth of penetration limits for light may not give adequate coverage for thicker lesions. At present, PDT dosimetry is far from being as quantitative as it is for any of the radiotherapy treatments. The possibility of salvage therapy of cancer recurrence cases is definitely the main attraction of PDT. However, the high cost of a new treatment center setup may not be justified until treatment regiments are quantified, optimized, and standardized, which may take many years of research and randomized clinical trials. Management of pain/discomfort is a challenge in a minority of patients. The possible intolerable pains for patients undergoing ALA-mediated skin cancer PDT can be significantly reduced by a two-segmented procedure with the first part of the light treatment performed using low light fluence rate , with the normal fluence rate used for the remainder of the treatment.14 This method is routinely used in many centers and can be well tolerated. For ALA and most of the second generation photosensitizers (such as BPD), phototoxicity usually dissipates within a week.15 Skin toxicity in particular is also significantly reduced compared to the first generation photosensitizer, Photofrin®, by shifting the wavelength further to the red, away from the peak wavelength of the sun. We agree that adequate PDT dosimetry (light, photosensitizers, and oxygen) is a key to successful clinical application of PDT. In the past decade, significant development has been made in understanding the models that describe the interaction among light, photosensitizer, and oxygen.2,5,15 Currently, the most commonly used quantity in clinical PDT is PDT dose, defined as the energy absorbed by the photosensitizer (or a product of photosensitizer and light fluence rate). PDT dose can be routinely determined in the clinical setting using in vivo dosimetry.15 Quantitative models that describe the production of singlet oxygen are emerging.16 Alternatively, implicit dosimetry5 (e.g., fluorescent photobleaching) can be used for PDT dosimetry.2 The fact that these methods of dosimetry are not currently in widespread use in PDT should be a cause for more physics involvement rather than a cause for discouragement of its clinical use.15 For nonmelanoma superficial skin cancers, PDT presents the same physical advantage of conformal dose coverage as inherent with electron therapy and brachytherapy treatments, but has the added advantage of using a nonionizing radiation. For deep seated skin cancers such as melanoma, megavoltage photon and electron beams are currently used. However, in principle, PDT can be used interstitially for thicker skin lesions, probably as a salvage treatment initially. Tumor targeting and treatment in radiotherapy of all types is achieved through imaging, precise treatment planning, and advanced delivery techniques. For PDT, different imaging approaches are needed since the chemical environment is of much greater importance to the success of treatment. While preferential photosensitizer uptake by the tumor tissue has been demonstrated, this is not always the case for systemically administered drugs.17 More recent topical photosensitizers resolve localization issues by being applied directly to the skin site, but the proper level of the drug uptake remains problematic. To ensure that the limited physical penetration depth of both light and topical photosensitizer do not compromise adequate coverage of the tumor volume, PDT can only be used for superficial lesions that are not heavily pigmented. Even though subsequent local retreatments are not contraindicated, for those skin cancers that do not achieve local control the first time, there may be distant metastasis beyond the local PDT capabilities. Having a sharp boundary between treated and untreated tissues is extremely advantageous if the precise extent of the region being treated is known. PDT presents a situation where the treatment outcome is determined by several interdependent parameters characterizing a highly heterogeneous environment. Thus, drug uptake and the dose of light are highly influenced by the tissue type; the oxygen level depends on the initial tissue oxygenation and the rate of oxygen depletion, which changes with the light fluence and as a result of PDT-induced hypoxia through vascular collapse.13 The common approach to clinical dosimetry of measuring the amount of administered photosensitizer and the incident light exposure is clearly inadequate. Therefore, the issues of imaging and dosimetry will remain fundamental limitations in the foreseeable future." @default.
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• W2018234088 title "PDT is better than alternative therapies such as brachytherapy, electron beams, or low-energy x rays for the treatment of skin cancers" @default.
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