Photodynamic Therapy

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Use of photodynamic therapy

Under the photo- or photodynamic therapy ( PDT ) is a procedure for the treatment of tumors and other tissue changes such as neovascularization with light in combination with a light-activatable substance, a so-called photosensitizer , and present in the tissue oxygen . This is done to the patientSuch a primarily non-toxic sensitizer or one of its metabolic precursors either systemically (distributed throughout the body) or locally administered, which is more or less dependent on certain properties of the tumor or the tissue change (such as increased cell growth, increased metabolic activity or increased blood flow) selectively accumulates in the tumor or the tissue change. After a certain waiting time, the tumor or the tissue change is irradiated with light of a suitable wavelength . In the process, photophysical processes produce toxic substances, especially reactive oxygen species, which damage the tumor or the tissue changes.

application areas

Photodynamic therapy is used in particular when the microstructures of the tissue to be treated have to be spared, as is the case in the gastrointestinal tract , brain or eye .

Ophthalmology

Photodynamic therapy is now used as a standard procedure in ophthalmology. For a long time, it was the only approved treatment method for certain forms of neovascularization under the retina (choroidal neovascularization), such as those found in e.g. B. in the wet form of age- related macular degeneration (AMD). In Germany, the benzoporphyrin derivative verteporfin is approved for the treatment of AMD, which can be activated with a special low-energy laser with a wavelength of 680 nm. The particular advantage of PDT in this area of ​​application is the direct accessibility of the treatment site (the retina ) with the PDT laser through the patient's pupil. The position and size of the irradiation field can also be checked directly through the reflection of the fundus that is possible at the same time during treatment . With the PDT, the newly formed vessels can be closed and thus further loss of vision can be avoided. At the same time, the photoreceptors of the retina and the underlying pigment epithelium are spared by the relatively low laser power. In the meantime, there are also drugs available for the above-mentioned ophthalmological indications that are injected directly into the eye ( intravitreally ), for example Avastin , Lucentis , pegaptanib or triamcinolone and do not have to be activated by lighting. Some of these drugs are also used in combination with PDT. In the case of eye tumors such as childhood retinoblastoma , the first attempts at PDT with the then new porphyrins were made as early as the 1980s, which, however, led to tissue damage in the eye due to the high doses to be used. PDT with newer photosensitizers such as Verteporfin is still in its infancy.

oncology

Compared to surgical treatment, photodynamic therapy offers the advantage of a non-invasive or minimally invasive procedure. In particular, the extensive removal of healthy tissue in the tumor area, which is necessary for safety reasons, is omitted. A radiation requires about ten to 100 minutes. Typical irradiance levels are 100 mW / cm 2 . The heating of the tissue is therefore only a few degrees Celsius . An anesthetic is only in the case of inaccessible internal organs necessary. The PDT of tumors is usually carried out in a single radiation session, but there is definitely the possibility of repetition. Since the irradiation takes place with normal light, the burden on the patient is relatively low compared to the "classic" therapy methods. A photodynamic treatment does not block the way for other therapeutic approaches; these can possibly still be carried out if complete healing has not been achieved.

The main disadvantage of photodynamic therapy is the low penetration depth of locally applied photosensitizer (or its metabolic precursor) of just a few millimeters and the limited penetration depth of light, so that usually only tumors that are not too advanced or that are growing over a large area can be treated successfully. Therefore, especially z. B. skin tumors such as actinic keratoses , the superficial (superficial) basalioma , but also warts as areas of application for photodynamic therapy. By using lasers in combination with optical fibers , tumors on surfaces within the body that are accessible endoscopically can also be treated. In addition, larger tumors can be treated by piercing such fibers into the tissue. However, this approach is rare.

Photodynamic treatment of internal tumors is far less common and is usually only palliative used such as in the esophagus , for bile duct - and gall bladder cancer or brain tumors .

If the photosensitizer is used not only locally but also systemically, a significant temporary sensitivity to light is to be expected as a side effect , which in individual cases can last for several weeks. The risk of the associated reduction in quality of life can be seen as an argument against therapy in the case of palliative use with a short life expectancy.

Although this process was investigated by Hermann von Tappeiner among others in Munich at the beginning of the 20th century , it was not until the 1980s that it became more widespread due to an improvement in photosensitizers and the use of lasers. Typical areas of application are tumors in the urinary bladder , in the outer head area, in the oral cavity , larynx , esophagus, in the lungs , in the bile duct and in the genital area .

dermatology

In dermatology, photodynamic therapy has found widespread use for the treatment of various types of skin cancer and their precursors. It is the first line treatment for mild and moderate actinic keratosis . Two metabolic precursors of the photosensitizer protoporphyrin IX for the treatment of actinic keratoses , 5-aminolevulinic acid (5-ALA) and its methyl ester, methyl 5-amino-4-oxopentanoate (MAOP), have been approved as medicinal products . MAOP has also been approved for the treatment of certain forms of basal cell carcinoma and Bowen's disease , for which the much newer drugs with 5-ALA have not yet been approved. 5-aminolevulinic acid is available in a nanoemulsion that optimizes skin penetration and in crystalline form as a drug plaster, MAOP as a cream. After external addition of 5-ALA, protoporphyrin IX accumulated four times more in isolated skin tumor cells than in healthy cells within an exposure time relevant for photodynamic therapy. The accumulation from 5-ALA in tumor cells was almost twice as high as that from the related precursor substance MAOP, but equally low in healthy cells for both active substances.

Smaller studies and individual case reports suggest the effectiveness of photodynamic therapy in circumscribed scleroderma , acne , psoriasis vulgaris, various hyperkeratoses , virus-related vulgar warts and other chronic skin diseases. In individual cases and small series of cases , photodynamic therapy “[...] was able to produce good results even in various forms of rosacea [...] after two to four uses. The effectiveness is probably due, among other things, to a stimulation of the immune system and an antimicrobial effect. ”It should be noted that this is not a standard therapy for rosacea, but is currently only of a purely experimental nature.

Since the photodynamic therapy using artificial light sources can be very painful, the photodynamic daylight therapy is increasingly used. 5-ALA or MAOP are applied to the affected areas of the skin. Then the patient is exposed to daylight for about 2 hours. This treatment is equally effective, but significantly less painful.

Veterinary medicine

Due to the surface effect of PDT (up to 0.3 cm), this therapy is successfully used e.g. B. in squamous cell carcinoma , but also in virus-induced skin diseases and diseases of the sebum glands and hair follicles .

Dentistry

A special form of PDT is antibacterial photodynamic therapy , which is mainly used in dentistry and used to destroy bacteria.

Biochemical basics

The photosensitizers used are predominantly porphyrins , which can be activated when exposed to red light at a wavelength of 630 nm to 635 nm. Often 5-aminolevulinic acid or its methyl ester, methyl 5-amino-4-oxopentanoate (MAOP), is used, metabolic precursors of protoporphyrin IX, which are increased, i.e. relatively selectively, converted into porphyrin in tumor cells or other tissue changes. Newer sensitizers can be stimulated at even greater wavelengths, with the advantage that the light penetrates the tissue somewhat more deeply.

Photosensitizers usually fluoresce and are therefore also used in the fluorescence diagnosis of tumors or other tissue changes. Photodynamic therapy (PDT) is therefore closely related to photodynamic diagnostics (PDD, fluorescence diagnostics (FD)). Under certain circumstances, photodynamic diagnostics can be carried out first with the same photosensitizer in the same session, followed immediately by photodynamic therapy.

The actual photophysical process takes place in several steps and requires the presence of oxygen , which is available in sufficient quantities in most cells. One molecule of the photosensitizer absorbs a photon of the light and is raised to the first excited singlet state. The longer the lifetime of this singlet state, the greater the probability of the rather seldom transition to an equally excited triplet state due to intercombination . Since optical transitions from this triplet state to the ground state are very unlikely, it has an unusually long lifespan. This enables contact with a particularly large number of molecules in the environment. If it hits a molecule whose ground state is a triplet state, an exchange of energy is possible, whereby both molecules change into a singlet state. One of the few molecules with a triplet ground state is molecular oxygen. Since the energy of the excited sensitizer molecule is greater than that required for a transition of the oxygen into an excited singlet state, this energy exchange can take place. The resulting singlet oxygen in turn has a particularly long service life with regard to an optical transition to the ground state. However, due to its ability to react chemically, it can damage cell components in the vicinity through oxidation . As a result, it can trigger necrosis or - by acting on the mitochondrial membrane - apoptosis .

Light sources used

The spectrum of the light source must be matched to the photosensitizer used and contain one or more excitation bands (absorption bands) of the photosensitizer.

For photodynamic therapy are used:

  • Broadband emitters ( e.g. halogen emitters )
  • Devices with light emitting diodes (LEDs)
  • Laser (monochromatic coherent light; especially in the field of ophthalmology)
  • Daylight (daylight can also be used as a light source - this applies to applications in dermatology)

With the broadband emitters, the visible light can be filtered. By choosing appropriate color filters, one or more excitation bands can be specifically selected for a specific photosensitizer, for example protoporphyrin IX (formed endogenously from applied 5-aminolevulinic acid (delta-aminolevulinic acid, ALA)). (Example with the absorption spectrum of protoporphyrin IX as well as the spectrum of a broadband emitter with the consequences of different filtering in the visible range on the excitation of protoporphyrin IX in.)

Related topics

In the genetically caused heme formation disorder erythropoietic protoporphyria , in which iron cannot be used with sufficient efficiency, the heme precursor protoporphyrin IX accumulates in tissue and in the skin. Those affected suffer from a greatly increased, painful intolerance to visible (sun) light, comparable to the side effects of PDT.

Web links

Individual evidence

Note on the order of the individual references in the text: If several individual references are given in a text passage, the most important individual references for this text passage or the most recent individual references with regard to the publication date are at the beginning of the specified individual references.

  1. ↑ G. Ackermann: Photophysical basics for fluorescence diagnosis of tumors of the skin. Regensburg 2001 (Regensburg, University, dissertation, 2001. PDF full text; 15 MB ( memento of the original from December 20, 2003 in the Internet Archive ) Info: The archive link has been inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. ). @1@ 2Template: Webachiv / IABot / www.bibliothek.uni-regensburg.de
  2. ↑ a b Lasse R. Braathen, Rolf-Markus Szeimies, Nicole Basset-Seguin, Robert Bissonnette, Peter Foley, David Pariser, Rik Roelandts, Ann-Marie Wennberg, Colin A. Morton: Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: An international consensus. In: Journal of the American Academy of Dermatology . Volume 56, No. 1, 2007, pp. 125-143, doi: 10.1016 / j.jaad.2006.06.006 .
  3. ^ Eggert Stockfleth, Helmut Kerl: Guidelines for the management of actinic keratosis. In: European Journal of Dermatology . Volume 16, No. 6, 2006, pp. 599–606, doi : 10.1684 / ejd.2006.0017 (currently not available) .
  4. ^ A b Andrea Stritt, Hans Friedrich Merk, Lasse Roger Braathen, Verena von Felbert: Photodynamic therapy in the treatment of actinic keratosis. In: Photochemistry and Photobiology. Volume 84, No. 2, 2008, pp. 388-398, doi: 10.1111 / j.1751-1097.2007.00276.x .
  5. ↑ a b V. von Felbert, G. Hoffmann, S. Hoff-Lesch F. Abuzahra, CN Renn, LR Braathen, HF Merk: Photodynamic therapy of multiple actinic keratoses: Reduced pain through use of visible light plus water-filtered infrared- A (wIRA) compared to light from light-emitting diodes. In: The British Journal of Dermatology. Volume 163, No. 3, 2010, pp. 607-615, doi: 10.1111 / j.1365-2133.2010.09817.x .
  6. ↑ a b Rolf-Markus Szeimies, Robert T. Matheson, Steven A. Davis, Ashish C. Bhatia, Yvonne Frambach, Winfried Klöveborn, Heike Fesq, Carola Berking, Julia Reifenberger, Diamant Thaçi: Topical methyl aminolevulinate photodynamic therapy using red light- emitting diode light for multiple actinic keratoses: a randomized study. In: Dermatologic Surgery . Volume 35, No. 4, 2009, pp. 586-592, doi: 10.1111 / j.1524-4725.2009.01096.x .
  7. ^ A b D. Fai, N. Arpaia, I. Romano, M. Vestita, N. Cassano, GA Vena: Methyl-aminolevulinate photodynamic therapy for the treatment of actinic keratoses. In: Giornale Italiano di Dermatologia e Venereologia . Volume 144, No. 3, 2009, pp. 281-285. PMID 19528909 .
  8. ^ A b C. Morton, S. Campbell, G. Gupta, S. Keohane, J. Lear, I. Zaki, S. Walton, N. Kerrouche, G. Thomas, P. Soto: Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. In: British Journal of Dermatology . Volume 155, No. 5, 2006, pp. 1029-1036. PMID 17034536 , doi: 10.1111 / j.1365-2133.2006.07470.x .
  9. ↑ a b Mikael Tarstedt, Inger Rosdahl, Berit Berne, Katarina Svanberg, Ann-Marie Wennberg: A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix) -PDT in actinic keratosis of the face and scalp. In: Acta Dermato-Venereologica . Volume 85, No. 5, 2005, pp. 424-428, doi : 10.1080 / 00015550510032887 (currently not available) . PMID 16159735 .
  10. Jump up ↑ Daniel J. Piacquadio, Diana M. Chen, Harold F. Farber, Joseph F. Fowler Jr, Scott D. Glazer, J. John Goodman, Luciann L. Hruza, Edward WB Jeffes, Mark R. Ling, Tania J. Phillips , Tena M. Rallis, Richard K. Scher, Charles R. Taylor, Gerald David Weinstein: Photodynamic therapy with aminolevulinic acid topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: investigator-blinded, phase 3 , multicenter trial. In: Archives of Dermatology . Volume 140, No. 1, 2004, pp. 41-46, doi: 10.1001 / archderm.140.1.41 .
  11. ↑ a b David M. Pariser, Nicholas J. Lowe, Daniel M. Stewart, Michael T. Jarratt, Anne W. Lucky, Robert J. Pariser, Paul S. Yamauchi: Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. In: Journal of the American Academy of Dermatology. Volume 48, No. 2, 2003, pp. 227-232, doi: 10.1067 / mjd.2003.49 .
  12. ↑ a b M. Freeman, C. Vinciullo, D. Francis, L. Spelman, R. Nguyen, P. Fergin, K.-E. Thai, D. Murrell, W. Weightman, C. Anderson, C. Reid, A. Watson, P. Foley: A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective , randomized study. In: Journal of Dermatological Treatment . Volume 14, No. 2, 2003, pp. 99-106, doi: 10.1080 / 09546630310012118 .
  13. ↑ C. Clark, A. Bryden, R. Dawe, H. Moseley, J. Ferguson, SH Ibbotson: Topical 5-aminolaevulinic acid photodynamic therapy for cutaneous lesions: outcome and comparison of light sources. In: Photodermatology, Photoimmunology & Photomedicine . Volume 19, 2003, pp. 134-141, doi: 10.1034 / j.1600-0781.2003.00024.x .
  14. ↑ a b c T. Dirschka, P. Radny, R. Dominicus, H. Mensing, H. Brüning, L. Jenne, L. Karl, M. Sebastian, C. Oster-Schmidt, W. Klövekorn, U. Reinhold, M. Tanner, D. Gröne, M. Deichmann, M. Simon, F. Hübinger, G. Hofbauer, G. Krähn-Senftleben, F. Borrosch, K. Reich, C. Berking, P. Wolf, P. Lehmann, M. Moers-Carpi, H. Hönigsmann, K. Wernicke-Panten, S. Hahn, G. Pabst, D. Voss, M. Foguet, B. Schmitz, H. Lübbert, RM Szeimies; AK-CT002 Study Group; AK-CT003 Study Group: Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. In: Br J Dermatol. 168 (4), Apr 2013, pp. 825-836. PMID 21910711
  15. ↑ a b c RM Szeimies, P. Radny, M. Sebastian, F. Borrosch, T. Dirschka, G. Krähn-Senftleben, K. Reich, G. Pabst, D. Voss, M. Foguet, R. Gahlmann, H Lübbert, U. Reinhold: Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a prospective, randomized, double-blind, placebo-controlled phase III study. In: Br J Dermatol. 163 (2), Aug 2010, pp. 386-394. PMID 20518784
  16. ↑ T. Maisch, F. Santarelli, S. Schreml, P. Babilas, RM Szeimies: Fluorescence induction of protoporphyrin IX by a new 5-aminolevulinic acid nanoemulsion used for photodynamic therapy in a full-thickness ex vivo skin model. In: Exp Dermatol. (19), 2010, pp. E302 – e305.
  17. ^ R. Schulten, B. Novak, B. Schmitz, H. Lübbert: Comparison of the uptake of 5-aminolevulinic acid and its methyl ester in keratinocytes and skin. In: Naunyn Schmiedebergs Arch Pharmacol. 385 (10), Oct 2012, pp. 969-979. doi: 10.1007 / s00210-012-0777-4 .
  18. ^ S1 guideline for rosacea from the German Dermatological Society (DDG). In: AWMF online . Working Group of the Scientific Medical Associations eV (AWMF eV), as of March 1, 2013, p. 18 ( PDF file ( Memento of the original from March 17, 2016 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please Check the original and archive link according to the instructions and then remove this note. , 127.93 KiB; the guideline refers to H. Nybaek / GB Jemec: Photodynamic therapy in the treatment of rosacea, in: Dermatology, 2005 with regard to the individual cases and the small case series , 211, 135-138 and LE Bryld / GB Jemec: Photodynamic therapy in a series of rosacea patients, in: J Eur Acad Dermatol Venerol, 2007, 21, 1199-1202 and regarding the presumption of effectiveness on T. Maisch / RM Szeimies / G. Jori / C. Abels: Antibacterial photodynamic therapy in dermatology, in: Photochem Photobiol Sci, 2004, 3, 907-917). @1@ 2Template: Webachiv / IABot / www.awmf.org
  19. ↑ Julia Buchholz, Barbara Kaser-Hotz: Combination of photodynamic therapy and hyperthermia with water-filtered infrared light for the treatment of cutaneous squamous cell carcinoma in 15 cats: A pilot study. In: Small Animal Practice. Volume 55, No. 5, 2010, ISSN  0023-2076 , pp. 248-254.
  20. ↑ a b c Silke M. Fuchs, Joachim W. Fluhr, Lora Bankova, Jörg Tittelbach, Gerd Hoffmann, Peter Elsner: Photodynamic therapy (PDT) and waterfiltered infrared A (wIRA) in patients with recalcitrant common hand and foot warts. In: German Medical Science. 2, 2004, Doc08, PMC 2703213 (free full text).