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Photodynamic therapy in the head and neck
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Fotokemisk behandling av tumörer inom huvud- och halsområdet (Swedish)
Abstract [en]

Photodynamic therapy, PDT, is a method to diagnose and treat cancer. In PDT a sensitizer is administered to the patient and this sensitizer is accumulated in tumors. If the sensitizer-containing tumor is subjected to a laser of a specific wavelength the tumor is fluorescing allowing diagnostics. If other wavelengths are used a process involving reactive oxygen species and singlet oxygen is started and the tumor cells are killed. This process thus requires oxygen as well.

This thesis investigates how UV-induced damage of the skin and different physiological factors of the skin influences the uptake of 5- aminolevulinic acid, ALA, and its conversion to the active sensitizer protoporphyrin IX, PpIX. It shows that UV-induced damage affects both the uptake and production of PpIX. UV-induced damage lowers the PpIX produced after ALA application both if the damage is acute and in chronically UV-affected skin.

The PpIX production differs inter and intra individually. When looking how different physiological factors affect the PpIX production after topically applied ALA the thesis shows that an increase of temperature increases the production. No correlation between the formation of PpIX and the density of hair follicles was found and a weak correlation was seen comparing the epidermal and total dermal thickness and PpIX production

The thesis also shows how PDT is used in treating laryngeal malignancies. It shows that it is possible to cure laryngeal tumors (both squamous cell carcinomas and sarcomas) using PDT primarily, and that the cure rate as well as outcome of voice and patient safety is comparable to the conventional treatment modalities.

PDT can also be used as a function and organ sparing treatment for recurring laryngeal cancers, both squamous cell carcinomas and sarcomas.

Place, publisher, year, edition, pages
Örebro: Örebro university , 2014. , 74 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 110
Keyword [en]
Photo Dynamic Therapy, Cancer, Skin, Larynx, 5-ALA, UVradiation, sarcoma, squamous cell carcinoma, porfimer sodium, temoporfin, voice
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:oru:diva-35953ISBN: 978-91-7529-039-3 (print)OAI: oai:DiVA.org:oru-35953DiVA: diva2:737767
Public defence
2014-09-19, Universitetssjukhuset, B-hus aulan, Södra Grev Rosengatan, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-08-14 Created: 2014-08-14 Last updated: 2017-10-17Bibliographically approved
List of papers
1. The influence of UV exposure on 5-aminolevulinic acid-induced protoporphyrin IX production in skin
Open this publication in new window or tab >>The influence of UV exposure on 5-aminolevulinic acid-induced protoporphyrin IX production in skin
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2001 (English)In: Photochemistry and Photobiology, ISSN 0031-8655, E-ISSN 1751-1097, Vol. 74, no 6, 825-828 p.Article in journal (Refereed) Published
Abstract [en]

The skin of nude mice was exposed to erythemogenic doses of UV radiation, which resulted in erythema with edema. An ointment containing 5-aminolevulinic acid (ALA) was topically applied on mouse and human skin. Differences in the kinetics of protoporphyrin accumulation were investigated in normal and UV-exposed skin. At 24 and 48 h after UV exposure, skin produced significantly less protoporphyrin IX (PpIX) than skin unexposed to UV. Human skin on body sites frequently exposed to solar radiation (the lower arm) also produced less PpIX than skin exposed more rarely to the sun (the upper arm). It is concluded that UV radiation introduces persisting changes in the skin, relevant to its capability of producing PpIX from ALA. The observed differences in ALA-induced PpIX fluorescence may be the result of altered penetration of ALA through the stratum corneum or altered metabolizing ability of normal and UV-exposed skin (or both).

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Molecular Cellbiology; Microbiology
Identifiers
urn:nbn:se:oru:diva-38179 (URN)10.1562/0031-8655(2001)0740825TIOUEO2.0.CO2 (DOI)000172863800012 ()11783939 (PubMedID)2-s2.0-0035790603 (Scopus ID)
Note

The present work was supported by the Research Foundation of the Norwegian Radium Hospital and by the Örebro Medical Center Hospital. The authors are thankful to Even Angell-Petersen and Saulius Bagdonas for their help during the experiment.

Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-12-05Bibliographically approved
2. Influence of physiological parameters on the production of protoporphyrin IX in human skin by topical application of 5-aminolevulinic acid and its hexylester
Open this publication in new window or tab >>Influence of physiological parameters on the production of protoporphyrin IX in human skin by topical application of 5-aminolevulinic acid and its hexylester
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2006 (English)In: Journal of Medical Sciences, ISSN 1682-4474, E-ISSN 1812-5727, Vol. 6, no 4, 546-553 p.Article in journal (Refereed) Published
Abstract [en]

Formation of protoporphyrin IX (PpIX) after topical application of 5-aminolevulinic acid (ALA) and its hexylester derivative (ALA-Hex) was studied on healthy human skin. Temperature, density of hair follicles, epidermal and skin thickness were measured on the application sites. The skin temperature was found to be the strongest determinant for PpIX formation. The PpIX fluorescence increase was about 25% per degree Celsius. Formation of PpIX was found to be independent of the density of hair follicles. A weak correlation was found between the PpIX fluorescence and the thickness of epidermis and skin. Sun exposure seems to reduce the production of PpIX slightly.

Keyword
5-aminolevulinic acid esters, Epidermal thickness, Fluorescence, Hair follicles, Skin physiology, Skin thickness, Spectroscopy, Temperature, aminolevulinic acid, aminolevulinic acid hexyl ester, protoporphyrin, adult, article, controlled study, correlation analysis, density, epidermis, fluorescence analysis, hair follicle, human, human experiment, male, normal human, ointment, protein synthesis, skin temperature, skinfold thickness, sun exposure, volunteer
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Microbiology; Molecular Cellbiology
Identifiers
urn:nbn:se:oru:diva-38183 (URN)10.3923/jms.2006.546.553 (DOI)- ()- (PubMedID)2-s2.0-33750387149 (Scopus ID)
Note

References: Baumgartner, R., Huber, R.M., Schulz, H., Stepp, H., Rick, K., Gamarra, F., Leberig, A., Roth, C., Inhalation of 5-aminolevulinic acid: A new technique for fluorescence detection of early stage lung cancer (1996) J. Photochem. Photobiol. B:Biol., 36, pp. 169-174; Bender, J., Ericson, M.B., Merclin, N., Iani, V., Rosen, A., Engstrom, S., Moan, J., Lipid cubic phases for improved topical drug delivery in photodynamic therapy (2005) J. Control Release, 106, pp. 350-360; Bissonnette, R., Shapiro, J., Zeng, H., McLean, D.I., Lui, H., Topical pbotodynamic therapy with 5-aminolaevulinic acid does not induce hair regrowth in patients with extensive alopecia areata (2000) Br. J. Dermatol., 143, pp. 1032-1035; Clark, C., Bryden, A., Dawe, R., Moseley, H., Ferguson, J., Ibbotson, S.H., Topical 5-aminolaevulinic acid photodynamic therapy for cutaneous lesions: Outcome and comparison of light sources (2003) Photodermatol. Photoimmunol. Photomed., 19, pp. 134-141; De Rosa, F.S., Tedesco, A.C., Lopez, R.F., Riemma Pierre, M.B., Lange, N., Marchetti, J.M., Gomes Rotta, J.C., Lopes Badra Bentley, M.B., In vitro skin permeation and retention of 5-aminolevulinic acid ester derivatives for photodynamic therapy (2003) J. Control. Rel., 89, pp. 261-269; Divaris, D.X., Kennedy, J.C., Pottier, R.H., Phototoxic damage to sebaceous glands and hair follicles of mice after systemic administration of 5-aminolevulinic acid correlates with localized protoporphyrin IX fluorescence (1990) Am. J. Pathol., 136, pp. 891-897; Dolmans, D.E., Fukumura, D., Jain, R.K., Photodynamic therapy for cancer (2003) Nat. Rev. Cancer, 3, pp. 380-387; Dougherty, T.J., Gomer, C.J., Henderson, B.W., Jori, G., Kessel, D., Korbelik, M., Moan, J., Peng, Q., Photodynamic therapy (1998) J. Natl. Cancer Inst., 90, pp. 889-905; Fischer, F., Dickson, E.F., Kennedy, J.C., Pottier, R.H., An affordable, portable fluorescence imaging device for skin lesion detection using a dual wavelength approach for image contrast enhancement and aminolaevulinic acid-induced protoporphyrin IX Part II. In vivo testing (2001) Lasers Med. Sci., 16, pp. 207-212; Foote, C.S., Definition of type I and type II photosensitized oxidation (1991) Photochem. Photobiol., 54, p. 659; Fritsch, C., Goerz, G., Ruzicka, T., Photodynamic therapy in dermatology (1998) Arch. Dermatol., 134, pp. 207-214; Gardlo, K., Ruzicka, T., Metvix (PhotoCure) (2002) Curr. Opin. Invest. Drugs, 3, pp. 1672-1678; Gaullier, J.M., Berg, K., Peng, Q., Anholt, H., Selbo, P.K., Ma, L.W., Moan, J., Use of 5-aminolevulinic acid esters to improve photodynamic therapy on cells in culture (1997) Cancer Res., 57, pp. 1481-1486; Gibson, S.L., Cupriks, D.J., Havens, J.J., Nguyen, M.L., Hilf, R., A regulatory role for porphobilinogen deaminase (PBGD) in δ-aminolaevulinic acid (δ-ALA)-induced photosensitization? (1998) Br. J. Cancer, 77, pp. 235-243; Juzenas, P., Juzeniene, A., Kaalhus, O., Iani, V., Moan, J., Noninvasive fluorescence excitation spectroscopy during application of 5-aminolevulinic acid in vivo (2002) Photochem. Photobiol. Sci., 1, pp. 745-748; Juzeniene, A., Juzenas, P., Kaalhus, O., Iani, V., Moan, J., Temperature effect on accumulation of protoporphyrin IX after topical application of 5-aminolevulinic acid and its methylester and hexylester derivatives in normal mouse skin (2002) Photochem. Photobiol., 76, pp. 452-456; Juzeniene, A., Juzenas, P., Iani, V., Moan, J., Topical application of 5-aminolevulinic acid and its methylester, hexylester and octylester derivatives: Considerations for dosimetry in mouse skin model (2002) Photochem. Photobiol., 76, pp. 329-334; Kalka, K., Merk, H., Mukhtar, H., Photodynamic therapy in dermatology (2000) J. Am. Acad. Dermatol., 42, pp. 389-413; Kelty, C.J., Brown, N.J., Reed, M.W., Ackroyd, R., The use of 5-aminolaevulinic acid as a photosensitiser in photodynamic therapy and photodiagnosis (2002) Photochem. Photobiol. Sci., 1, pp. 158-168; Kennedy, J.C., Pottier, R.H., Pross, D.C., Photodynamic therapy with endogenous protoporphyrin IX: Basic principles and present clinical experience (1990) J. Photochem. Photobiol. B, 6, pp. 143-148; Kennedy, J.C., Pottier, R.H., Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy (1992) J. Photochem. Photobiol., B, 14, pp. 275-292; Kennedy, J.C., Marcus, S.L., Pottier, R.H., Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photo sensitization induced by 5-aminolevulinic acid (ALA): Mechanisms and clinical results (1996) J. Clin. Laser Med. Surg., 14, pp. 289-304; Kloek, J., Akkermans, W., Beijersbergen Van Henegouwen, G.M., Derivatives of 5-aminolevulinic acid for photodynamic therapy: Enzymatic conversion into protoporphyrin (1998) Photochem. Photobiol., 67, pp. 150-154; Konan, Y.N., Gurny, R., Allemann, E., State of the art in the delivery of photosensitizers for photodynamic therapy (2002) J. Photochem. Photobiol., B, 66, pp. 89-106; Krieg, R.C., Messmann, H., Rauch, J., Seeger, S., Knuechel, R., Metabolic characterization of tumor cell-specific protoporphyrin IX accumulation after exposure to 5-aminolevulinic acid in human colonic cells (2002) Photochem. Photobiol., 76, pp. 518-525; Lang, K., Lehmann, P., Bolsen, K., Ruzicka, T., Fritsch, C., Aminolevulinic acid: Pharmacological profile and clinical indication (2001) Expert. Opin. Investig. Drugs, 10, pp. 1139-1156; Lange, N., Jichlinski, P., Zellweger, M., Forrer, M., Marti, A., Guillou, L., Kucera, P., van den Bergh, H., Photodetection of early human bladder cancer based on the fluorescence of 5-aminolaevulinic acid hexylester-induced protoporphyrin IX: A pilot study (1999) Br. J. Cancer, 80, pp. 185-193; Leunig, A., Mehlmann, M., Betz, C., Stepp, H., Arbogast, S., Grevers, G., Baumgartner, R., Fluorescence staining of oral cancer using a topical application of 5-aminolevulinic acid: Fluorescence microscopic studies (2003) J. Photochem. Photobiol. B:Biol., 60, pp. 44-49; Liang, M.T., Norris, S., Effects of skin blood flow and temperature on bioelectric impedance after exercise (1993) Med. Sci. Sports Exerc., 25, pp. 1231-1239; Lopez, R.F., Lange, N., Guy, R., Bentley, M.V., Photodynamic therapy of skin cancer: Controlled drug delivery of 5-ALA and its esters (2004) Adv. Drug Deliv. Rev., 56, pp. 77-94; Ludicke, F., Gabrecht, T., Lange, N., Wagnieres, G., van den Bergh, H., Berclaz, L., Major, A.L., Photodynamic diagnosis of ovarian cancer using hexaminolaevulinate: A preclinical study (2003) Br. J. Cancer, 88, pp. 1780-1784; Malik, Z., Lugaci, H., Destruction of erythroleukaemic cells by photoactivation of endogenous porphyrins (1987) Br. J. Cancer, 56, pp. 589-595; McCarron, P.A., Donnelly, R.F., Andrews, G.P., Woolfson, A.D., Stability of 5-aminolevulinic acid in novel non-aqueous gel and patch-type systems intended for topical application (2005) J. Pharm. Sci., 94, pp. 1756-1771; Merclin, N., Bender, J., Sparr, E., Guy, R.H., Ehrsson, H., Engstrom, S., Transdermal delivery from a lipid sponge phase - Iontophoretic and passive transport in vitro of 5-aminolevulinic acid and its methyl ester (2004) J. Control Release, 100, pp. 191-198; Moan, J., Peng, Q., Sorensen, R., Iani, V., Nesland, I.M., The biophysical foundations of photodynamic therapy (1998) Endoscopy, 30, pp. 387-391; Moan, J., Berg, K., Gadmar, O.B., Iani, V., Ma, L., Juzenas, P., The temperature dependence of protoporphyrin IX production in cells and tissues (1999) Photochem. Photobiol., 70, pp. 669-673; Moan, J., van den Akker, J.H.T.M., Juzenas, P., Ma, L.W., Angell-Petersen, E., Gadmar, Ø.B., Iani, V., On the basis for tumor selectivity in the 5-aminolevulinic acid-induced synthesis of protoporphyrin IX (2001) J. Porphyr. Phthalocyanines, 5, pp. 170-176; Morton, C.A., Brown, S.B., Collins, S., Ibbotson, S., Jenkinson, H., Guidelines for topical photodynamic therapy: Report of a workshop of the British Photodermatology Group (2002) Br. J. Dermatol., 146, pp. 552-567; Morton, C.A., The emerging role of 5-ALA-PDT in dermatology: Is PDT superior to standard treatments? (2002) J. Dermatolog. Treat., 13, pp. S25-S29; Ochsner, M., Photophysical and photobiological processes in the photodynamic therapy of tumours (1997) J. Photochem. Photobiol., B, 39, pp. 1-18; Peng, Q., Evensen, J.F., Rimington, C., Moan, J., A comparison of different photosensitizing dyes with respect to uptake C3H-tumors and tissues of mice (1987) Cancer Lett., 36, pp. 1-10; Peng, Q., Warloe, T., Berg, K., Moan, J., Kongshaug, M., Giercksky, K.E., Nesland, J.M., 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges (1997) Cancer, 79, pp. 2282-2308; Peng, Q., Warloe, T., Moan, J., Godal, A., Apricena, F., Giercksky, K.E., Nesland, J.M., Antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy can be enhanced by the use of a low dose of photofrin in human tumor xenografts (2001) Cancer Res., 61, pp. 5824-5832; Pottier, R.H., Chow, Y.F., LaPlante, J.P., Truscott, T.G., Kennedy, J.C., Beiner, L.A., Non-invasive technique for obtaining fluorescence excitation and emission spectra in vivo (1986) Photochem. Photobiol., 44, pp. 679-687; Sharfaei, S., Juzenas, P., Moan, J., Bissonnette, R., Weekly topical application of methyl aminolevulinate followed by light exposure delays the appearance of UV-induced skin tumours in mice (2002) Arch. Dermatol. Res., 294, pp. 237-242; Spikes, J.D., Photodynamic action: From Paramecium to Photochemotherapy (1997) Photochem. Photobiol., 65 S, pp. 142S-147S; Stefanidou, M., Tosca, A., Themelis, G., Vazgiouraki, E., Balas, C., In vivo fluorescence kinetics and photodynamic therapy efficacy of δ-aminolevulinic acid-induced porphyrins in basal cell carcinomas and actinic keratoses; Jimplications for optimization of photodynamic therapy (2000) Eur. J. Dermatol., 10, pp. 351-356; Uehlinger, P., Zellweger, M., Wagnieres, G., Juillerat-Jeanneret, L., van den Bergh, H., Lange, N., 5-Aminolevulinic acid and its derivatives: Physical chemical properties and protoporphyrin IX formation in cultured cells (2000) J. Photochem. Photobiol. B, 54, pp. 72-80; van der Veen, N., de Bruijn, H.S., Berg, R.J., Star, W.M., Kinetics and localisation of PpIX fluorescence after topical and systemic ALA application, observed in skin and skin tumours of UVB-treated mice (1996) Br. J. Cancer, 73, pp. 925-930; van den Akker, J.T.H.M., de Bruijn, H.S., Beijersbergen Van Henegouwen, G.M., Star, W.M., Sterenborg, H.J., Protoporphyrin IX fluorescence kinetics and localization after topical application of ALA pentyl ester and ALA on hairless mouse skin with UVB-induced early skin cancer (2000) Photochem. Photobiol., 72, pp. 399-406; van den Akker, J.T.H.M., Holroyd, J.A., Vernon, D.I., Sterenborg, H.J., Brown, S.B., Comparative in vitro percutaneous penetration of 5-aminolevulinic acid and two of its esters through excised hairless mouse skin (2003) Lasers Surg. Med., 33, pp. 173-181; van den Akker, J.T.H.M., Boot, K., Vernon, D.I., Brown, S.B., Groenendijk, L., van Rhoon, G.C., Sterenborg, H.J., Effect of elevating the skin temperature during topical ALA application on in vitro ALA penetration through mouse skin and in vivo PpIX production in human skin (2004) Photochem. Photobiol. 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Sci., 12, pp. 182-199; Winkler, A., Muller-Goymann, C.C., The influence of topical formulations on the permeation of 5-aminolevulinic acid and its n-butyl ester through excised human stratum corneum (2005) Eur. J. Pharm. Biopharm., 60, pp. 427-437

Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-12-05Bibliographically approved
3. Outcome of primary treatment of early laryngeal malignancies using photodynamic therapy
Open this publication in new window or tab >>Outcome of primary treatment of early laryngeal malignancies using photodynamic therapy
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2014 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 134, no 8, 852-858 p.Article in journal (Refereed) Published
Abstract [en]

Conclusion: Photodynamic therapy (PDT) is a viable and safe option for early laryngeal cancer that would be less suitably treated with radiation or trans-oral laser surgery (TLS). The cure rates with PDT appear to be comparable to those of conventional therapy, and the voice outcomes are also comparable. In the case of many sarcomas, PDT appears to be an organ- and function-sparing therapy, although it is more costly than other treatments.

Objectives: The aim of this study was to show the results of PDT when it is used as a primary treatment of early laryngeal cancer. Methods: We studied the results of PDT when used as a primary treatment. We looked at survival, effect on tumor, side effects, voice, and costs.

Results: The follow-up period was a median of 59 months. Nine of 10 patients were cured of their laryngeal cancer. PDT alone cured seven patients. All four of the sarcomas were cured using temoporfin. Two of three tumors that involved the anterior commissure were cured using only interstitial illumination with PDT. No serious side effects were noted. The patient's voices were improved after treatment in 5 of 10 cases, and none had a worsened voice.

Keyword
Cancer, larynx, PDT, sarcoma, squamous cell carcinoma, porfimer sodium, temoporfin, voice
National Category
Otorhinolaryngology
Research subject
Oto-Rhino-Laryngology
Identifiers
urn:nbn:se:oru:diva-36374 (URN)10.3109/00016489.2014.906748 (DOI)000340137200013 ()24856450 (PubMedID)2-s2.0-84904327200 (Scopus ID)
Available from: 2014-09-03 Created: 2014-09-03 Last updated: 2017-12-05Bibliographically approved
4. Outcome of treatment of recurring laryngeal malignancies using photodynamic therapy
Open this publication in new window or tab >>Outcome of treatment of recurring laryngeal malignancies using photodynamic therapy
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:oru:diva-38185 (URN)
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-10-17Bibliographically approved

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