Photodynamic Therapy Photodynamic therapy (PDT) is a newly emerging form of therapy that has great potential in the areas of cancer, age related macular degeneration, psoriasis and a host of other chronic diseases that have frustrated physicians through-out the ages. Despite the wealth of literature (over 10,000 scientific papers), few physicians outside the specialty areas of Ophthalmology and Dermatology are familiar with this treatment modality and the underlying mode of action. This review will attempt to illuminate this fascinating and revolutionary gift to mankind. Basics of PDT The basic elements of PDT are as simple as 1-2-3: Photosensitiser + Visible light + Oxygen = Tissue Response. The unique property of photosensitisers to selectively accumulate in malignant and dysplastic tissues is exploited in the treatment of malignancies. Once the drugs are in place, the light is used to irradiate the tissues with a fixed frequency light source unique to each drug and disease. The drug absorbs the light, which stimulates the drug to destroy only the diseased tissues in which the drug has been absorbed. 1.Light-activated drug is applied topically or injected intravenously. 2.Drug accumulates in the affected tissue. 3.Low power light is delivered through the Illuminating device and focused on the affected tissue. 4.Light activates photo reactive drug, releasing agents that destroy only affected cells. How PDT selectively destroys tumors is a simple concept. The PDT agents, mainly porphrins and their derivatives, preferentially accumulate in neoplastic tissue. This occurs either from selective up-take or delayed elimination relative to normal tissue. When the Photosensitiser is activated by a light source (laser or filament), the molecule absorbs the light energy. In this excited state it is extremely reactive and interacts with molecular oxygen to produce highly reactive oxygen "singlet". This moiety is highly cytotoxic. Since the agent is concentrated in the tumor and the light is directed at the mass, the resulting direct tumorocidal activity and micro vascular damage destroys tumor cells. The result is inflammation and necrosis of the cancer. If the cancer is adjacent to a cavity or lumen (esophagus, bronchus, intestinal tract or bladder) the treated tissue sloughs away and there is normal healing and re-epithelialisation of the affected site. Since this PDT process is a "cold" photochemical process, there is essentially no thermal damage to the tissues; connective tissue (collagen and elastin) and vasculature are largely spared. Compared to surgery and conventional thermal Yag and argon laser treatment, there is much less damage and disruption of the underlying and adjacent normal tissue structures. Both the patient and clinician have much to benefit from this approach. Superficial treatments do not require sterile theatre conditions and can be delivered in an outpatient setting. There is little post-treatment discomfort and the only significant side effect is residual photosensitivity (protection from direct sunlight is necessary for a period of time). Method of Administration and Treatment PDT agents can be administered either systemically or topically. Following a period of time to allow the Photosensitiser to accumulate in the target tissue, low intensity light of the appropriate wavelength is directed into the tumor. The depth and effectiveness of the treatment is contingent upon several factors. Longer wavelengths of light achieve greater depths of penetration into the tissue; thus allowing more effective treatment of deeper tumors. Also, the efficiency of converting light energy into tumorocidal reactive ‘singlet’ oxygen varies greatly between PDT agents. Newer agents show higher efficiency in this regard. For example, the second-generation agent temoporfin is 100 times more efficient in creating ‘singlets’ compared to the older approved agent Photofrin. It also is more selectively concentrated in tumor cells and is activated at a longer wavelength. All this will translate into improved treatment results for patients. PDT Applications At present, photodynamic therapy is in use or under investigation for both oncology and nononcology areas of medicine and surgery. Oncology PDT has significant potential in the management and treatment of malignant tumors. Photofrin, a ‘first’ generation agent, is approved for use in the palliation and treatment of lung, esophageal, gastric, gall bladder, cervical and bladder cancer in various countries throughout the world. Foscan, a ‘second’ generation Photosensitiser, has been assigned FDA fast track designation for approval .5-ALA (a naturally occurring amino acid) has also recently been approved by the FDA for use in actinic pre-malignant skin lesions. In numerous studies, ALA has been shown to be very successful in basal and squamous cell carcinoma of the skin and other forms of cutaneous malignancy. A recent article in Lancet Oncology Vol 1 December 2000 by Colin Hopper stated: "Compared with standard approaches, PDT can achieve equivalent or greater efficacy in the treatment of many cancers, particularly in the head and neck and basal-cell carcinoma, with greatly reduced morbidity and disfigurement. The technique is simple, can commonly be carried out in outpatient clinics, and is highly acceptable to patients. PDT is not confined to the treatment of small superficial tumors. It can be repeated to debulk large tumors progressively, and can also be applied through interstitial light delivery to large solid tumors. PDT is currently approved in the palliation of locally advanced cancers and a few early-stage diseases, but we should now consider its potential in situations that capitalize on the strengths of the technique. These include first-line treatment in early malignant and premalignant disease, adjuvant therapy for surgery, and interstitial treatment of deep-seated tumours." PDT can be utilized before or after surgery, chemotherapy and/or ionizing radiation therapy. None of these other therapies are compromised by PDT and unlike the latter treatment, can be repeated many times with no resistance developing, minimal morbidity and better functional results. Excellent cosmetic outcome with PDT makes it important in skin lesions and cancer of the head and neck where preserving function and respecting delicate underlying structures is critical. Treatment of extensive areas of pleura and peritoneum can likewise be treated with relative ease, unlike radiation, which would result in unacceptable damage to underlying tissues. The adjunctive use of PDT at the time of surgical removal of a primary tumor may valuable to aid in the elimination of residual microscopic metastases. Finally, innovative uses of interstitial light delivery (light is delivered by inserting fiberoptic bundles through needles directed into the tumor mass under image guidance) have allowed a subcutaneous tumor 60 cubic centimeters to be successfully treated with Photofrin. Aside from care to avoid major blood vessels, this minimally invasive treatment is applicable to most areas of the body. Barrett’s Esophagus and cervical dysplasia are examples of conditions associated with frequent progression to malignancy. PDT has been found in numerous studies to be a successful treatment for high-grade dysplasia of the esophagus and Japan has already approved Photofrin for use in cervical dysplasia. Conclusion Photodynamic therapy (PDT) is a minimally invasive treatment with great promise in malignant disease, age related macular degeneration and a host of other chronic disease processes. Although it represents an entirely new modality of treatment and is mostly unfamiliar to many established physicians, the potential benefits deserve careful consideration and study. The Photodynamic Treatment Center At East Clinic Pascal Carmody Medical Director William Porter M.D. PDT Killaloe, Co. Clare, Ireland Tele: 353 (0) 61 376349/376206 Fax: 353 (0) 61 376773 www.info@photodynamictreatment.com LINK to East Clinic in Killaloe, Eire PDT information Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. 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