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What is PDT and how is it used

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What is PDT and how is it used ...

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 Basics2005). 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

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

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 Dermatologist2006).

    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

    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.

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,

    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

    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

     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

    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

    Foscan2003).

    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.

    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

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