"What is PDT and how is it Used?", Rutaganira


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"What is PDT and how is it Used?", Rutaganira

  1. 1. What is PDT and how is it Used? Florentine Rutaganira IST8A Winter 2007 March 14, 2007 Abstract PDT is an approach to biophotonics that uses chemicals, called photosensitisers, and light to selectively destroy cancer cells. It is a minimally invasive alternative to extensive surgery, which removes much healthy tissue. FDA restrictions on photosensitisers and light techniques limit the widespread application of PDT to the public sector. Current public uses of PDT are in cosmetic surgery and wet macular degeneration. Success in recent clinical trials ensures PDT’s implementation in other areas of cancer treatment. Advances in PDT will come from new photosensitisers, improved light sources, and different applications of the treatment. I. What is Biophotonics and how is PDT related? From its beginnings, medicine has relied on techniques that kill living structures in order to diagnose and treat health problems. Now, however, biophotonics presents a new approach to the practice of medicine. It deals with the relation of biological material to light, for which the photon is its quantum unit. By using light, one is able to image, analyze, and manipulate living tissue in a minimally invasive manner. In addition, biophotonics allows for study in the cellular and molecular region (“Introduction and Basics” 2005). Combining the advantages of biophotonics with recent advances in biomedical science, medical doctors are now able to handle situations that were formerly believed impossible. Due to their recent development, many techniques in biophotonics have yet to reach the public sector. However, some of these
  2. 2. techniques, including photodynamic therapy (PDT), have been approved. Through the use of light sources and photosensitisers, cancer cells can be destroyed. Its current success has influenced substantial recent research in the area of PDT. II. Mechanisms in PDT The two main components of PDT are the light source and the photosensitiser. Depending on the area of treatment, photosensitisers are injected into the patient’s bloodstream or applied onto their skin. Photosensitisers alone are harmless; they do not react directly with cells and tissues. After they are absorbed by cancer cell, usually within a couple of days, light is applied to the area of treatment. The light causes the photosensitiser, a light-sensitive drug, to react with oxygen and form a chemical that kills nearby cancer cells. The absorption spectrum and color play an important role because the photosensitiser relies on absorption to operate. Red light’s efficacy in penetrating tissue makes it the desired choice. However, the FDA only approves blue-light treatment, which is less effective at penetrating tissue than red light treatment (“Photodynamic Therapy for the Dermatologist” 2006). PDT utilizes any light source, either laser or non-laser, with suitable spectral characteristics, and a high output at an absorption maximum of the photosensitiser. Choosing between a laser and a non-laser source depends on the size of the lesion and the cost. For small lesions, laser PDT has many advantages. The monochromaticity of lasers provides maximum effectiveness if the wavelength of the laser corresponds with the peak absorption of the photosensitiser. Lasers produce a high amount of electromagnetic radiation for a small amount of surface area, minimizing the exposure time. With fiber optics, lasers can deliver light to any organ. However, laser treatment is costly. When treating large skin lesions, non-coherent light
  3. 3. sources are superior to lasers because of their large illumination fields. Non-coherent light sources are also smaller, readily available, and relatively cheap. Their polychromaticity allows for use of different photosensitisers with different absorption maxima. Given the appropriate combination of drug and light, non-coherent sources may be just as effective as laser sources (“Photodynamic Therapy for the Dermatologist” 2006). Figure 1. Injection of Photosensitiser. http://www.bmb.leeds.ac.uk/pdt/images/4man/4man1.gif Figure 2. Photosensitiser concentrates in cancer cells. http://www.bmb.leeds.ac.uk/pdt/images/4man/4man2.gif
  4. 4. Figure 3: Light applied to target area. http://www.bmb.leeds.ac.uk/pdt/images/4man/4man3.gif Figure 4: Cancer is destroyed. http://www.bmb.leeds.ac.uk/pdt/images/4man/4man4.gif Figures one through four show the process of PDT. First, the photosensitiser is injected (Figure 1). After time, the photosensitiser concentrates in cancer cells (Figure 2). Light is directed on the target area concentrated with the photosensitiser, and a chemical reaction occurs (Figure 3). The cancer is now destroyed (Figure 4). The underlying concept of PDT is relatively easy to understand; variables in the light source and photosensitiser make the technique complex.
  5. 5. III. PDT Applications A. FDA Approved Photosensitisers Due to its recent emergence, PDT is not widely used in medicine. Two common photosensitizing agents have been approved by the FDA: Porfimer Sodium (Photofrin) and Aminolevulinic acid. The photosensitiser of choice depends on the location and type of cancer. 1. Porfimer Sodium Porfimer Sodium is given intravenously, and it travels through the bloodstream to be absorbed by all cells in the body. Normal cells get rid of most of the Porfirmer Sodium within a couple of days, but the drug remains concentrated in cancer cells and in skin cells. Laser light is directed at cancer cells using a fiber optic after two days, allowing the normal cells to get rid of the Porfimer Sodium. The laser is a low-power light, so it does not burn and there is little or no pain during the procedure. The light is applied for 5 to 40 minutes, depending on the size of the tumor that is being treated. Porfimer Sodium is currently used to treat esophageal cancer (“PDT Using Porfimer Sodium” 2005). 2. Aminolevulinic Acid Aminolevulinic acid (ALA) is applied topically and does not reach other parts of the body. The lesions become sensitive to light, while the rest of the body does not. A non-laser, blue light source is directed at the lesion for 15 minutes. After treatment, the lesion may scale and crust for a few days before healing. The lesion then falls off (“PDT Using Aminolevulinic Acid (ALA). ” 2005). ALA is currently used to treat actinic keratosis lesions. B. Cosmetic Surgery Skin damage is one of the most prevalent conditions treated by dermatologists. PDT improves patients’ cosmetic outlook. In cosmetic surgery, PDT is used to treat acne, rosacea,
  6. 6. and sun damage to the skin. A typical PDT treatment begins with a short contact microdermabrasion which removes any dead skin cells on the surface of the face, allowing for a better application of the photosensitiser. Aminolevulinic acid (ALA) is applied and left in place for 30 to 60 minutes. ALA is removed using an alcohol swab, soap and water. Lastly, the patient is treated with a light source. Acne treatments with PDT have positive effects in significant numbers of individuals. FDA approved blue light sources improve inflammatory acne in just a few short sessions without side effects, unlike current uses of antibiotics or isotretinoin. PDT has also successfully treated rosacea, a common skin condition that causes redness and swelling on the face and thickening of the skin. Oral and Topical antibiotic treatment helps to reduce the blood vessels and redness associated with rosacea, but PDT is more successful. Dermatologist Mark Steven Nestor, MD, PHD is impressed with PDT’s results: “Photodynamic therapy is an essentially painless procedure for the patient. While initial results may be seen as early as the first session, some patients require a series of three to five sessions to see significant results. However, it really depends on the patient and the severity of the skin condition being treated” (“Photodynamic Therapy Sheds Light on Treatment of Acne, Rosacea, and Sun Damage” 2003). C. Wet Macular Degeneration
  7. 7. Figure 5. Macular Degeneration and Process of Laser Treatment. http://www.eyemdlink.com/images/illustrations/small/focal_laser_amd.jpg Photodynamic therapy (PDT) currently treats choroidal neovascular membranes (CNVM), the leaky vascular structures under the retina, in the "wet" form of age related macular degeneration (AMD), shown in Figure 5. Visudyne (verteporfin), a photosensitiser, is administered intravenously, and perfuses the CNVM and remainder of the body. The ophthalmologist treats the CNVM with a red laser at 689nm for about 90 seconds. This non-thermal laser light activates the Visudyne, and produces an active form of oxygen that both coagulates and reduces the growth of abnormal blood vessels, without damaging nearby ocular tissues. This process prevents the leakage of fluid from the CNVM, but the photosensitiser increases the patient’s chance of potentially severe sunburn on the eyes and the skin for 5 days (“Photodynamic Therapy for Wet Macular Degeneration” 2006). In FDA studies involving "wet" macular degeneration and treatment with PDT, patients had initial vision between 20/40 and 20/200. Treatment was limited by the size of the lesion and old scars of the retina were not treated. 70% of patients had stabilization of their vision with treatment, and 14% had visual improvement. Patients with better initial vision had greater success with the treatment; patients with long standing "wet" macular degeneration which has led to scarring, had less success. PDT is not a cure for CNVM, but it provides a stabilization of vision. IV. The Future of PDT
  8. 8. Advancements in photodynamic therapy will result from the use of new photosensitizing agents, different lasers, and new applications of the treatment. With advancements in PDT, more types of cancer will be treated. A. New Photosensitisers and Light Sources There is an increase in demand for photosensitisers which are good absorbers of red light, have specific properties of tissue distribution, and do not cause the skin photosensitivity seen with current photosensitisers. New photosensitisers may extend treatment to deeper areas in the body, and may be more selective for cancer cells. By concentrating in cancer cells faster, the time needed between getting the drug and directing light will decrease. The adverse effect from selective photosensitisers is increased skin photosensitivity, which increases the amount of time that patients must stay out of sunlight and ultraviolet light following treatment. Researchers are also looking at different types of light sources. Newer photosensitisers may respond to smaller doses of light, leading to fewer side effects (“The Future of Photodynamic Therapy” 2005). B. New Applications Recent research in refractive epilepsy and pleural mesothelioma shows the advantage of using PDT combined with surgery. A collaborative project between the UC Davis Medical Center, Lawrence Livermore National Laboratory, and the University of Toronto is developing an approach to treating patients with refractive epilepsy using PDT. Refractive epilepsy is unresponsive to conventional anti-seizure medications. Surgery is currently the only method used to cure patients with this disorder. Limitations in neuroimaging methods and microsurgical techniques require doctors to remove healthy brain tissue during resection. Dr. Edie Zusman, a neurosurgeon at UCD identified the selective uptake of ALA and subsequent protoporphyrin IX (PpIX) fluorescence in a “kindling” model of epilepsy in rats. PpIX is used commercially as a
  9. 9. photosensitizing agent and it is activated with 630nm light. If successful, this project will allow for minimally invasive brain surgery to treat refractory epilepsy (“Biophotonic Approach to Refractory Epilepsy ” 2006). In a phase I clinical study, PDT was combined with surgery to treat pleural mesothelioma. Twenty-six patients with malignant pleural mesothelioma completed the PDT treatment. Seven of the patients had portions of the lung, the lining of the lung, the lining of the heart, and the diaphragm removed via Extrapleural pneumonectomy. The remaining nineteen patients only had portions of the lining of the lung removed via pleurectomy. Patients received Foscan (meta-tetrahydroxyphenyclorin, mTHPC) as a photosensitiser. Four different doses of Foscan were administered and four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose. The maximally tolerated dose was 0.1mg per kg of Foscan combined with 652nm of light. Fourteen patients had no complications. Two out of three patients who received high Foscan doses died. Other patients developed wound burns and skin sensitivity. The trial proved a success: it found the best way to give Foscan safely, determined the side effects of Foscan, and proved that Foscan-mediated PDT may allow some patients to undergo a lung-sparing pleurectomy rather than the more invasive Extrapleural pneumonectomy. The results of the clinical trial warranted a Phase II study (“A phase I study of Foscan…” 2003). C. New Cancer Treatments There are other studies on several types of cancer and precancerous conditions including cancers of the skin, cervix, bladder, prostrate, bile duct, pancreas, stomach, brain, head and neck.
  10. 10. Figure 6. Surgeons use a fiber optic for PDT in the operating room. http://upload.wikimedia.org/wikipedia/en/thumb/c/c6/Photodynamic_therapy.jpg/300px- PDT may be used to help treat larger solid tumors by using optics and needles, as shown in Figure 6. Many cancers are in deep areas that cannot be reached by light through the skin. Fiber optics may be the solution to treating these areas. V. The Pros and Cons of PDT Studies show that PDT can be as effective as surgery or radiation therapy when treating certain kinds of cancers and precancerous conditions. It is less invasive than surgery and can be targeted very precisely. It also can be repeated several times at the same site if necessary, with less scarring than surgery. If the target area cannot be reached by light directly, PDT can be effectively used in combination with surgery. PDT also has its limitations. Its reliance on light confines treatment to areas where light can reach, regardless of the photosensitiser used. It is mainly used for cosmetic purposes or in
  11. 11. the lining of internal organs rather than treating extensive cancers (“What is Photodynamic Therapy (PDT)?” 2005). Current photosensitisers in use increase the skins sensitivity to light, restricting patients from exposure to sunlight and ultraviolet light after treatment. Lastly, public uses of PDT are limited to topical therapy due to its recent debut. PDT is better than alternative treatments. However it is still largely an experimental therapy and is only available to a very small range of patients. More research is needed to further develop PDT’s techniques and its appliations to the clinical setting. References (2003-10-22), “Photodynamic Therapy Sheds Light on Treatment of Acne, Rosacea, and Sun Damage”, American Academy of Dermatology. Retrieved on 2007-02-01. (2005-02-08). The Future of Photodynamic Therapy. American Cancer Society. Retrieved on 2007-02-01. (2005-02-08). PDT Using Aminolevulinic Acid (ALA). American Cancer Society. Retrieved on 2007-02-01. (2005-02-08). PDT Using Porfimer Sodium. American Cancer Society. Retrieved on 2007-02- 01. (2005-02-08). What is Photodynamic Therapy (PDT)? American Cancer Society. Retrieved on 2007-02-01. (2006). Photodynamic Therapy for Wet Macular Degeneration. EyeMDLink. Retrieved on 2007-02-01. Lague, Andrew. (2006-07-28). Biophotonic Approach to Refractory Epilepsy – NSF Center for Biophotonics. Regents of the University of California. Retrieved on 2007-02-01. Lague, Andrew. (2005-11-08). Introduction and Basics – NSF Center for Biophotonics. Regents of the University of California. Retrieved on 2007-02-01. Surg, Ann Thorac. (2003-03), “A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma”, Entrez PubMed. Retrieved on 2007-02-01.
  12. 12. Rao, Jaggi. (2006) Photodynamic Therapy for the Dermatologist. WebMD. Retrieved on 2007- 02-01. Figure 1. (2003-06-08). The Photosensitiser is given by injection. Centre for Photobiology and Photodynamic Therapy. Retrieved on 2007-02-01. Figure 2. (2003-06-08). Photosensitisers Concentrate in Tumor Tissue. Centre for Photobiology and Photodynamic Therapy. Retrieved on 2007-02-01. Figure 3. (2003-06-08). Activation by Light. Centre for Photobiology and Photodynamic Therapy. Retrieved on 2007-02-01. Figure 4. (2003-06-08). Destruction of the Tumor. Centre for Photobiology and Photodynamic Therapy. Retrieved on 2007-02-01. Figure 5. (2006). Laser Treatment of Wet Macular Degeneration. EyeMDLink. Retrieved on 2007-02-01. Figure 6. (2007-01-11). Shown is Close up of Surgeons…. Wikipedia. Retrieved on 2007-02- 01.