Key Terms: Actinic keratosis, Barrett's esophagus, Bronchi, Fiberoptics, Free radicals, Hematoporphyrin, Nanometer, Orphan drug, Palliative.
Definition
Photodynamic therapy (PDT) is a form of nonsurgical cancer treatment available since the early 1990s that combines a photosensitizing medication with exposure to a laser or other specific light wavelength to kill cancer cells. It can be used before or after surgery and other forms of cancer treatment. In some cases, PDT can even be administered during surgery to kill any cancer cells that were not removed by excision.
Purpose
Photodynamic therapy is still evolving, both in terms of the types of cancer it is approved to treat and the specific drugs that are used. PDT with a drug called porfimer sodium (Photofrin) was first approved as a treatment for esophageal cancer in 1995. The Food and Drug Administration (FDA) then extended its approval of this drug to cover non-small cell lung cancer in 1998. As of the early 2000s, the FDA has also approved porfimer sodium for the treatment of tumors located in the bronchi of the lungs and for palliative treatment of advanced cancers of the esophagus. Some cancer centers in the United States administer PDT with porfimer sodium for the treatment of certain types of skin cancer (squamous cell carcinoma, basal cell carcinoma, and Bowen's disease), recurrences of breast cancer following mastectomy, colorectal cancer, and cancers of the vulva and cervix, but these applications of PDT are still considered experimental as of early 2005.
In December 1999, the FDA approved a compound called aminolevulinic acid (ALA or Levulan Kerastick) for the treatment of actinic keratosis, a precancerous skin disorder caused by sun exposure. Experimental uses of ALA, as of the early 2000s, include treatment of mycosis fungoides and cancerous tumors on the surface of the skin.
Porfimer sodium and ALA are the only photosensitizing agents approved by the FDA for use in the United States as of 2005; however, several newer drugs for PDT are being tested in cancer centers in the United States and Europe. The most important of these will be described below.
In addition to cancer therapy, PDT is used to treat such conditions as wet macular degeneration, an eye disorder that can lead to blindness, as well as such benign skin conditions as psoriasis, acne, and skin disorders caused by the human papilloma virus. In addition, PDT is under investigation as a possible treatment for certain forms of coronary artery disease.
Precautions
Precautions for porfimer sodium (Photofrin):
- Porfimer sodium cannot be used in patients who are allergic to hematoporphyrin, a blood pigment used to make the drug.
- It cannot be used in pregnant or nursing women because its safety during pregnancy or lactation has not been established.
- It cannot be used to treat children.
- Lung tumors treated with Photofrin must be located in an airway where the doctor can reach them with a brochoscope.
- Photofrin cannot be used to treat tumors in the esophagus or bronchi that are beginning to break into the patient's windpipe or a major blood vessel. The drug should also be used cautiously in treating bronchial tumors that could block the airway if they develop inflammation following PDT.
- Patients who are receiving radiotherapy should not have PDT with porfimer sodium until 4 weeks after their last radiation treatment. They should also not be treated with radiotherapy until 2–4 weeks after a PDT treatment.
Precautions for aminolevulinic acid (ALA):
- Patients being treated with ALA must protect their skin from exposure to sunlight or bright indoor light in the short time period between application of the drug to the skin and the PDT treatment.
- ALA should be used cautiously in pregnant women or nursing mothers.
- If a second treatment is necessary, it should not be done before eight weeks after the first treatment.
Description
How Pdt Works
Photodynamic therapy is based on a series of chemical reactions involving a specific wavelength of visible light, a photosensitizing drug, and oxygen. There is no standard wavelength of light, light source, exposure period, or method of administering the medication that covers all forms of PDT. Most photosensitizing drugs are given intravenously, but some are applied to the skin or taken by mouth. Photosensitizers given by injection are activated by light in the red portion of the visible light spectrum, around 630–700 nanometers (nm; a nanometer is a measure of length, one billionth of a meter), while those applied to the skin are usually activated by blue light.
In general, cancerous tumors inside the body need more concentrated doses of light than abnormal growths on the body surface. Lasers are usually used to deliver highly concentrated light at one specific wavelength, while light sources that provide a larger area of illumination, such as light-emitting diodes (LEDs), are more efficient for treating skin tumors.
In contrast to their uses in surgery, lasers are not used in PDT to remove tissue or seal blood vessels with heat; rather they are used to start a chemical reaction. As a result, they do not become hot enough to burn tissue. The burning or stinging sensation that some patients experience during PDT is caused by the release of oxygen stimulating nearby nerve endings rather than heat from the laser itself.
Lasers can be attached to fiberoptics for treating tumors inside the body. Fiberoptics are thin strands of plastic or glass with special optical properties that can be threaded through a bronchoscope or endoscope, which are special tubes that allow the doctor to see into the patient's lungs or esophagus. Light from the laser is then transmitted along the special fibers to the tumor, thus allowing the doctor to activate the photosensitizing medication in a very small area of tissue without damaging normal tissue nearby.
PDT is a two-step form of therapy. First, the photosensitizing medication is injected into a vein or applied to the skin several days or hours before the scheduled treatment. The drug is absorbed by all body tissues but remains in cancer cells longer than in normal cells because the cancer cells are multiplying faster. After the medication has had time to collect in the malignant cells, the doctor directs a light source of the proper wavelength on the targeted area. When the light source strikes tissue containing the photosensitizing medication in the presence of oxygen, the medication is activated and produces free radicals and a highly reactive form of oxygen called singlet oxygen. The free radicals and singlet oxygen interact with the cell membranes of the cancer cells to destroy the energy-producing structures inside the cancer cells. In addition to killing the cancer cells directly, PDT works by closing blood vessels inside the tumor, thereby shutting off its supply of nutrients, and by stimulating the immune system to produce interleukins (nonantibody proteins) and other substances that attack the cancer.
Photosensitizing Drugs
PORFIMER SODIUM Porfimer sodium, or Photofrin, was the first medication used for PDT. It is a purified derivative of hematoporphyrin, a dark reddish-purple pigment found in blood. Photofrin is activated by red light at a wavelength of 630 nm; one disadvantage of this short wavelength is that it cannot penetrate tissue deeper than about a third of an inch, thus making Photofrin unsuitable for treating tumors that lie deep beneath the surface. The light used to activate Photofrin is usually generated by a laser.
Porfimer sodium has several other disadvantages for PDT: It is a complex chemical mixture that tends to break down over time; it has limited ability to penetrate tissue; and it takes 4–6 weeks to be cleared from the skin, thus leaving patients susceptible to a photosensitivity reaction for a long period of time after their PDT treatment. A photosensitivity reaction occurs when sensitized skin is exposed to sunlight or other bright light and is characterized by redness, swelling, and blistering of the exposed skin. As a result of Photofrin's disadvantages, researchers have been studying other photosensitizers with the following characteristics:
- They are single compounds rather than mixtures of chemicals.
- They are more effective in absorbing the red region of the visible light spectrum.
- They are more selective in targeting malignant tissue.
- They are more efficient in generating singlet oxygen.
Aminolevulinic Acid
Aminolevulinic acid, or ALA, is a short-lived photosensitizer that is applied to the skin as a 5–20% oil-in-water mixture. It is activated by either a special blue light illuminator or by light at 630–635 nm.
Second-Generation Photosensitizers
Newer photosensitizing agents that are being used in clinical trials as of 2005 include:
- HPPH (2-[1-hexyloethyl]-2-devinyl-pyropheophorbidea; brand name Photochlor). HPPH is a photosensitizer that is activated by light more efficiently than Photo-frin. In addition, patients treated with HPPH do not have the long-term photosensitivity reactions associated with Photofrin. HPPH has been used experimentally since 2003 at the Roswell Park Cancer Institute in Buffalo, New York, to treat esophageal cancer, Barrett's esophagus, basal cell carcinoma, and recurrent breast cancer following mastectomy. It is also under-going clinical trials in schools of veterinary medicine as a possible treatment for cancers in cats and dogs. Like Photofrin, HPPH is given intravenously.
- Verteporfin (also known as BPD-MA [benzoporphyrin derivative monoacid ring A]; brand name Visudyne). Verteporfin is a second-generation photosensitizer used primarily to treat eye disorders, including age-related macular degeneration, other abnormal formations of blood vessels within the eye, and histoplasmosis (an eye infection caused by a fungus). Verteporfin is also being investigated as a possible treatment for skin cancer and psoriasis.
- Temoporfin (Meta-tetra hydroxyphenyl chlorin; brand name Foscan). Temoporfin is a chlorin-type photosensitizer developed in the United Kingdom. It was approved by the European Union in 2001 for the treatment of head and neck cancers and certain types of lung cancer, but is categorized as an orphan drug in the United States. The FDA lists temoporfin as an orphan drug for the palliative treatment of inoperable head and neck cancers.
- Motexafin lutetium (brand name Lu-Tex). Lu-Tex is an injectable dye that has been used in clinical trials to treat malignant melanoma. It has a high degree of selectivity for cancer cells. It also shows promise as a treatment for recurrent breast cancer and atherosclerosis.
Clinical Trials
Although the National Cancer Institute (NCI) is not conducting trials of new PDT drugs as of 2005, there are several cancer centers in the United States and Canada that are investigating Photochlor and other second-generation photosensitizers.
Preparation
Pdt for Skin Conditions
A patient receiving PDT for skin cancer or a precancerous skin disorder will have ALA applied to the affected area 3–6 hours before the scheduled treatment. The skin may or may not be covered with a dressing. The patient does not need to fast or make any other special preparations. If the affected area of skin is on the face, the patient may be given goggles to wear to protect the eyes from the blue light used to activate the drug.
Pdt for Internal Cancers
The photosensitizing agents used for PDT or palliative treatment of esophageal or lung cancers are given by injection, usually 2–3 days before treatment. The patient may return home after the injection, but must avoid sunlight and bright light indoors before the light treatment. The patient does not need to fast or discontinue other medications, but should cover the windows and skylights in their home before receiving the light treatment to prevent exposure to bright light after returning home.
Patients undergoing PDT for esophageal or lung cancers are given a local or general anesthetic before the doctor inserts the bronchoscope or endoscope. They may also be given a mild tranquilizer to relieve anxiety.
Aftercare
Aftercare following PDT with porfimer sodium involves 4–6 weeks of protection from sunlight and other sources of bright light, including tanning lamps or the examination lamps found in doctors' and dentists' offices. During this period, the patient should wear dark glasses; long-sleeved shirts of light-colored, and tightly woven fabric long pants or slacks; and a wide-brimmed hat to protect the skin and eyes outdoors for at least 30 days after treatment. Sunscreen creams and lotions do not provide enough protection. It is best to run necessary errands after sundown or ask someone else in the household to drive the car. Women should not use helmet-type hair dryers or hand-held dryers on a high setting, as the drug remains in the scalp for several weeks and may cause burns if exposed to high heat. Exposure to low levels of indoor light is necessary, however, in order to break down the Photofrin remaining in the skin. After 30 days, the doctor will give the patient instructions on testing the skin for any remaining sensitivity to light.
Patients who have received PDT for cancers in the lining of the bronchi must return two days after the treatment for a follow-up bronchoscopy, in which the doctor will remove dead tumor cells and other pieces of tissue from the treated area. This follow-up procedure is necessary to prevent inflammation and possible blockage of the patient's airway. Treated tumor sites require between 4 and 8 weeks for complete healing.
Patients who receive PDT with ALA do not need to take special precautions regarding sun exposure after treatment because the drug is short-lived. The treated skin will usually form a crust or scale for several days before healing completely.
Risks
Porfimer Sodium
Risks of PDT with porfimer sodium include photosensitivity reactions if the patient fails to observe the guidelines for aftercare; chest pain or a burning sensation in the chest or throat; difficulty swallowing; itching; the formation of ulcers or scar tissue; and discomfort in the eyes when exposed to sunlight, bright lights, or car headlights. Breast cancer and lung cancer patients who have severe chest pain after PDT can be given medications to control the pain.
Aminolevulinic Acid
Some patients experience a stinging or burning sensation in the skin during the blue light treatment, but this usually goes away as soon as the light is turned off. Some patients also report temporary swelling or redness of the skin in the treated areas, or minor changes in the pigmentation of their skin.
Normal Results
Normal results of PDT of the esophagus or the lining of the bronchi are shrinkage of the tumor and destruction of cancer cells. Normal results of palliative treatment for cancer of the esophagus are sufficient shrinkage of the tumor to allow the patient to swallow again.
Normal results for PDT of the skin include shrinkage and destruction of the tumor, although large skin tumors may require a second treatment for complete removal.
Questions to Ask Your Doctor
- Is photodynamic therapy a possible treatment option for my cancer?
- Are you experienced in treating patients with PDT?
- Should I consider enrolling in a clinical trial of a new PDT drug?
Abnormal Results
Abnormal results include allergic reactions to the photosensitizing medication or failure of the tumor to respond to PDT.
Resources
Books
"Esophageal Tumors." Section 3, Chapter 34 in The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 2004.
Periodicals
Bellnier, David A., William R. Greco, Gregory M. Loewen, et al. "Population Pharmacokinetics of the Photodynamic Therapy Agent 2-[1-Hexyloethyl]-2-devinyl-Pyropheophorbide-a in Cancer Patients." Cancer Research 63 (April 15, 2003): 1806–1813.
Dimofte, A., T. C. Zhu, S. M. Hahn, and R. A. Lustig. "In vivo Light Dosimetry for Motexafin Lutetium-Mediated PDT of Recurrent Breast Cancer." Lasers in Surgery and Medicine 31 (2002): 305–312.
Fulton, James Jr., MD, PhD. "Actinic Keratosis." eMedicine, 12 November 2003.
Patti, Marco, MD, and Robert Li, MD. "Esophageal Cancer." eMedicine, 14 June 2004.
Suthamjariya, Kittisak, MD, and Charles R. Taylor, MD. "Photodynamic Therapy for the Dermatologist." eMedicine, 20 August 2002.
Other
American Cancer Society (ACS), Making Treatment Decisions. What Is Photodynamic Therapy?.
Food and Drug Administration (FDA). FDA Talk Paper T03-60, 4 August 2003. "FDA Approves Photofrin for Treatment of Pre-Cancerous Lesions in Barrett's Esophagus."
Guyton, Kate Z., PhD, Ellen Richmond, MS, and Ernest T. Hawk, MD. (National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases) Report of the Barrett's Esophagus Working Group. Bethesda, MD: NCI, 2001.
National Cancer Institute (NCI). Cancer Facts: Photodynamic Therapy for Cancer: Questions and Answers. Bethesda, MD: NCI, 2004.
National Cancer Institute (NCI). Oropharyngeal Cancer (PDQÛ): Treatment.
Roswell Park Cancer Institute. Photodynamic Therapy (PDT) Center. Buffalo, NY: Roswell Park Cancer Institute, 2005.
—Rebecca Frey, PhD
