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Aktuelle Urol 2007; 38(6): 455-462
DOI: 10.1055/s-2007-980149
Übersicht
© Georg Thieme Verlag Stuttgart · New York

Fluoreszenzdiagnostik und Photodynamische Therapie in der Urologie

Fluorescence Diagnosis and Photodynamic Therapy in UrologyH.  Stepp1 , R.  Waidelich2
  • 1Laser-Forschungslabor, LIFE-Zentrum, Klinikum der Universität München
  • 2Urologische Klinik, Klinikum der Universität München
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Publication History

Publication Date:
12 November 2007 (online)

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Zusammenfassung

Als Domäne der Endoskopie ist die Urologie eines der bedeutendsten Forschungsgebiete für den Einsatz photodynamischer Verfahren. Im Jahr 2005 erreichte die lange, erfolgreiche Tradition der Photodynamik in der Urologie mit der Zulassung von Hexaminolävulinat (HAL, Hexvix®) für die Fluoreszenzzystoskopie einen weiteren Meilenstein. Bisher zeigen alle Studien eine höhere Sensitivität der Fluoreszenzzystoskopie im Vergleich mit der konventionellen Zystoskopie unter Weißlichtbetrachtung beim Tumornachweis, insbesondere bei der Detektion des Carcinoma in situ. Die Mehrzahl randomisierter, zweiarmiger Studien bescheinigt der Fluoreszenzzystoskopie zudem signifikant geringere Residualtumor- und Rezidivraten. Selektive Tumorfluoreszenz kann auch im Nierenparenchym und in der Prostata beobachtet werden. Eine intraoperative Fluoreszenzkontrolle könnte es damit erleichtern, hohe Raten von R0-Resektionen zu erzielen. Neben dem diagnostischen ist auch das therapeutische Potenzial der Photodynamik hervorzuheben. Es reicht von der Rezidivprophylaxe beim Harnblasenkarzinom bis zur interstitiellen Therapie des Prostatakarzinoms. Zur Photodynamischen Therapie des Harnblasenkarzinoms gibt es bereits klinische Erfahrungswerte, Studien in den anderen Anwendungsbereichen befinden sich derzeit in Vorbereitung. Mit einem Überblick über die Methode und die bisher erzielten klinischen Ergebnisse und Einschätzungen soll dem Leser die Basis für eine eigene Beurteilung an die Hand gegeben werden.

Abstract

Urology is a preferential domain of endoscopy and as such an important research field for photodynamic procedures. An important milestone in the long-lasting and successful history of “photodynamics” in urology is the European approval of hexaminolevulinate (HAL, Hexvix®) for fluorescence cystoscopy. All clinical studies carried out so far have demonstrated a significant increase in sensitivity of fluorescence versus standard cystoscopy for the detection of bladder cancer, especially concerning carcinoma in situ. The majority of the randomised, two-armed studies additionally show significantly reduced rates of residual tumour and recurrences. Tumor-selective fluorescence can also be observed in the kidney and prostate. Intraoperative fluorescence detection might thus simplify the achievement of high rates of R0 resections. Apart from the diagnostic potential of “photodynamics”, also some possible therapeutic indications will be mentioned, including photodynamic therapy of bladder cancer and prostate cancer. Whereas initial clinical experience has been obtained for photodynamic therapy of bladder cancer, clinical studies for other indications are currently being designed. By providing an overview over methods and procedures as well as hitherto the available clinical results, we hope to provide reader with a basis for obtaining his/her own judgement.

Schlüsselwörter

Photodynamische Therapie - Fluoreszenzdiagnostik - Fluoreszenzzystoskopie - Aminolävulinsäure - Hexaminolävulinat - Hexvix - Phototoxizität - Photosensibilisator - Harnblasenkarzinom

Key words

Photodynamic therapy - fluorescence - cystoscopy - aminolevulinic acid - hexaminolevulinate - phototoxicity - photosensitizers - bladder cancer

Literatur

  • 1 Haukaas S, Daehlin L, Maartmann-Moe H, Ulvik N M. The long-term outcome in patients with superficial transitional cell carcinoma of the bladder: a single-institutional experience.  BJU Int. 1999;  83 957-963
    Search in Google Scholar
  • 2 Soloway M S, Sofer M, Vaidya A. Contemporary management of stage T1 transitional cell carcinoma of the bladder.  J Urol. 2002;  167 1573-1583
    Search in Google Scholar
  • 3 Witjes J A. Bladder carcinoma in situ in 2003: state of the art.  Eur Urol. 2004;  45 142-146
    Search in Google Scholar
  • 4 Jichlinski P. New diagnostic strategies in the detection and staging of bladder cancer.  Curr Opin Urol. 2003;  13 351-355
    Search in Google Scholar
  • 5 Allison R R, Bagnato V S, Cuenca R, Downie G H, Sibata C H. The future of photodynamic therapy in oncology.  Future Oncol. 2006;  2 53-71
    Search in Google Scholar
  • 6 Huang Z. A review of progress in clinical photodynamic therapy.  Technol Cancer Res Treat. 2005;  4 283-293
    Search in Google Scholar
  • 7 Pottier R, Krammer B, Stepp H, Baumgartner R. (editors) .Photodynamic Therapy with ALA, A Clinical Handbook. Cambridge: RSC Publishing 2006
    Search in Google Scholar
  • 8 Fotinos N, Campo M A, Popowycz F, Gurny R, Lange N. 5-Aminolevulinic acid derivatives in photomedicine: Characteristics, application and perspectives.  Photochem Photobiol. 2006;  82 994-1015
    Search in Google Scholar
  • 9 Batlle A M. Porphyrins, porphyrias, cancer and photodynamic therapy - a model for carcinogenesis.  J Photochem Photobiol B. 1993;  20 5-22
    Search in Google Scholar
  • 10 Marti A, Jichlinski P, Lange N. et al . Comparison of aminolevulinic acid and hexylester aminolevulinate induced protoporphyrin IX distribution in human bladder cancer.  J Urol. 2003;  170 428-432
    Search in Google Scholar
  • 11 Tappeiner H V. Die photodynamische Erscheinung. In: Asher L, Spiro K (eds). Ergebnisse der Physiologie Wiesbaden: Verlag von J. F. Bergmann 1909: 698-741
    Search in Google Scholar
  • 12 Jocham D, Staehler G, Baumgartner R, Unsold E. [Integral photodynamic therapy of multifocal bladder cancer. Initial clinical experiences].  Urologe A. 1985;  24 316-319
    Search in Google Scholar
  • 13 Tappeiner H V, Jesionek A. Therapeutische Versuche mit fluoreszierenden Stoffen.  Muench Med Wochenschr. 1903;  47 2042-2044
    Search in Google Scholar
  • 14 Dougherty T J. Photosensitization of malignant tumors.  Semin Surg Oncol. 1986;  2 24-37
    Search in Google Scholar
  • 15 Nseyo U O, Dougherty T J, Boyle D G. et al . Whole bladder photodynamic therapy for transitional cell carcinoma of bladder.  Urology. 1985;  26 274-280
    Search in Google Scholar
  • 16 Loidl W, Schmidbauer J, Susani M, Marberger M. Flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection and surveillance?.  Eur Urol. 2005;  47 323-326
    Search in Google Scholar
  • 17 Witjes J A, Moonen P M, Heijden A G van der. Comparison of hexaminolevulinate based flexible and rigid fluorescence cystoscopy with rigid white light cystoscopy in bladder cancer: results of a prospective Phase II study.  Eur Urol. 2005;  47 319-322
    Search in Google Scholar
  • 18 Jichlinski P, Guillou L, Karlsen S J. et al . Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer - a multicenter study.  J Urol. 2003;  170 226-229
    Search in Google Scholar
  • 19 Jocham D, Witjes F, Wagner S. et al . Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study.  J Urol. 2005;  174 862-866
    Search in Google Scholar
  • 20 Hungerhuber E, Stepp H, Kriegmair M. et al . Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder.  Urology. 2007;  69 260-264
    Search in Google Scholar
  • 21 Fradet Y, Grossman H B, Gomella L. et al . A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study.  J Urol. 2007;  178 68-73
    Search in Google Scholar
  • 22 Grossman H B, Gomella L, Fradet Y. et al . A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer.  J Urol. 2007;  178 62-67
    Search in Google Scholar
  • 23 Zaak D, Kriegmair M, Stepp H. et al . Endoscopic detection of transitional cell carcinoma with 5-aminolevulinic acid: results of 1012 fluorescence endoscopies.  Urology. 2001;  57 690-694
    Search in Google Scholar
  • 24 Zaak D, Hungerhuber E, Schneede P. et al . Role of 5-aminolevulinic acid in the detection of urothelial premalignant lesions.  Cancer. 2002;  95 1234-1238
    Search in Google Scholar
  • 25 Hendricksen K, Moonen P M, der Heijden A G, Witjes J A. False-positive lesions detected by fluorescence cystoscopy: any association with p53 and p16 expression?.  World J Urol. 2006;  24 597-601
    Search in Google Scholar
  • 26 Filbeck T, Roessler W, Knuechel R, Straub M, Kiel H J, Wieland W F. 5-aminolevulinic acid-induced fluorescence endoscopy applied at secondary transurethral resection after conventional resection of primary superficial bladder tumors.  Urology. 1999;  53 77-81
    Search in Google Scholar
  • 27 Grimbergen M C, Swol C F van, Jonges T G, Boon T A, Moorselaar R J van. Reduced specificity of 5-ALA induced fluorescence in photodynamic diagnosis of transitional cell carcinoma after previous intravesical therapy.  Eur Urol. 2003;  44 51-56
    Search in Google Scholar
  • 28 Hartmann A, Moser K, Kriegmair M, Hofstetter A, Hofstaedter F, Knuechel R. Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma.  Am J Pathol. 1999;  154 721-727
    Search in Google Scholar
  • 29 Kriegmair M, Zaak D, Rothenberger K H. et al . Transurethral resection for bladder cancer using 5-aminolevulinic acid induced fluorescence endoscopy versus white light endoscopy.  J Urol. 2002;  168 475-478
    Search in Google Scholar
  • 30 Riedl C R, Daniltchenko D, Koenig F, Simak R, Loening S A, Pflueger H. Fluorescence endoscopy with 5-aminolevulinic acid reduces early recurrence rate in superficial bladder cancer.  J Urol. 2001;  165 1121-1123
    Search in Google Scholar
  • 31 Denzinger S, Burger M, Walter B. et al . Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study.  Urology. 2007;  69 675-679
    Search in Google Scholar
  • 32 Filbeck T, Pichlmeier U, Knuechel R, Wieland W F, Roessler W. Clinically relevant improvement of recurrence-free survival with 5-aminolevulinic acid induced fluorescence diagnosis in patients with superficial bladder tumors.  J Urol. 2002;  168 67-71
    Search in Google Scholar
  • 33 Alken P, Siegsmund M, Gromoll-Bergmann K, Daffner P, Fenner W, Spelz J. A randomized controlled multicentre trial to compare the effects of transurethral resection of bladder carcinomas under 5-ALA induced fluorescence light to conventional white light. Poster presented at Annual EAU congress, March 21 - 24, 2007. Berlin, Germany 2007
    Search in Google Scholar
  • 34 Babjuk M, Soukup V, Petrik R, Jirsa M, Dvoracek J. 5-aminolaevulinic acid-induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer.  BJU Int. 2005;  96 798-802
    Search in Google Scholar
  • 35 Daniltchenko D I, Riedl C R, Sachs M D. et al . Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study.  J Urol. 2005;  174 2129-2133, discussion
    Search in Google Scholar
  • 36 Penkoff H, Steiner H, Dajc-Sommerer E. et al .Transurethral Detection and Resection of Bladder Carcinomas Under White or 5-ALA Induced Fluorescence Light: Results of the First Double-Blind Placebo-Controlled Clinical Trial. Abstract 1085 presented at Annual AUA congress, May 19 - 24, 2007. Anaheim, CA 2007
    Search in Google Scholar
  • 37 Rick K, Sroka R, Stepp H. et al . Pharmacokinetics of 5-aminolevulinic acid-induced protoporphyrin IX in skin and blood.  Journal of Photochemistry and Photobiology B: Biology. 1997;  40 313-319
    Search in Google Scholar
  • 38 Klem B, Lappin G, Nicholson S. et al . Determination of the bioavailability of [14C]-hexaminolevulinate using accelerator mass spectrometry after intravesical administration to human volunteers.  J Clin Pharmacol. 2006;  46 456-460
    Search in Google Scholar
  • 39 Colapaoli L, Thorsen J, Nopp A, Guttormsen A B. A case of anaphylactic shock possibly caused by intravesical Hexvix.  Acta Anaesthesiol Scand. 2006;  50 1165-1167
    Search in Google Scholar
  • 40 Avritscher E B, Cooksley C D, Grossman H B. et al . Clinical model of lifetime cost of treating bladder cancer and associated complications.  Urology. 2006;  68 549-553
    Search in Google Scholar
  • 41 Koenig F, Knittel J, Stepp H. Diagnosing cancer in vivo.  Science. 2001;  292 1401-1413
    Search in Google Scholar
  • 42 Jichlinski P, Leisinger H J. Photodynamic therapy in superficial bladder cancer: past, present and future.  Urol Res. 2001;  29 396-405
    Search in Google Scholar
  • 43 Beyer W. Systems for light application and dosimetry in photodynamic therapy.  J Photochem Photobiol B. 1996;  36 153-156
    Search in Google Scholar
  • 44 Staveren H J van, Keijzer M, Keesmaat T. et al . Integrating sphere effect in whole-bladder wall photodynamic therapy: III. Fluence multiplication, optical penetration and light distribution with an eccentric source for human bladder optical properties.  Phys Med Biol. 1996;  41 579-590
    Search in Google Scholar
  • 45 Beyer W, Waidelich R, Knuechel R, Stepp H, Baumgartner R, Hofstetter A. Technical concepts for white light photodynamic therapy of bladder cancer.  Medical Laser Application. 2002;  17 37-40
    Search in Google Scholar
  • 46 Waidelich R, Beyer W, Knuechel R. et al . Whole bladder photodynamic therapy with 5-aminolevulinic acid using a white light source.  Urology. 2003;  61 332-337
    Search in Google Scholar
  • 47 Jichlinski P. Photodynamic applications in superficial bladder cancer: facts and hopes!.  J Environ Pathol Toxicol Oncol. 2006;  25 441-451
    Search in Google Scholar
  • 48 Waidelich R, Stepp H, Baumgartner R, Weninger E, Hofstetter A, Kriegmair M. Clinical experience with 5-aminolevulinic acid and photodynamic therapy for refractory superficial bladder cancer.  J Urol. 2001;  165 1904-1907
    Search in Google Scholar
  • 49 Bader M, Zaak D, Stief C. et al .Photodynamic Therapy of bladder cancer - a phase I study using hexyl-aminolevulinate. Poster presented at Annual EAU congress, March 21 - 24, 2007. Berlin, Germany 2007
    Search in Google Scholar
  • 50 Shackley D C, Briggs C, Gilhooley A. et al . Photodynamic therapy for superficial bladder cancer under local anaesthetic.  BJU Int. 2002;  89 665-670
    Search in Google Scholar
  • 51 Tauber S, Stepp H, Meier R, Bone A, Hofstetter A, Stief C. Integral spectrophotometric analysis of 5-aminolaevulinic acid-induced fluorescence cytology of the urinary bladder.  BJU Int. 2006;  97 992-996
    Search in Google Scholar
  • 52 Pytel A, Schmeller N. New aspect of photodynamic diagnosis of bladder tumors: fluorescence cytology.  Urology. 2002;  59 216-219
    Search in Google Scholar
  • 53 Waidelich R, Hofstetter A, Stepp H, Baumgartner R, Weninger E, Kriegmair M. Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of upper tract urothelial tumors.  J Urol. 1998;  159 401-404
    Search in Google Scholar
  • 54 Schneede P, Munch P, Wagner S, Meyer T, Stockfleth E, Hofstetter A. Fluorescence urethroscopy following instillation of 5-aminolevulinic acid: a new procedure for detecting clinical and subclinical HPV lesions of the urethra.  J Eur Acad Dermatol Venereol. 2001;  15 121-125
    Search in Google Scholar
  • 55 Zaak D, Hofstetter A, Frimberger D, Schneede P. Recurrence of condylomata acuminata of the urethra after conventional and fluorescence-controlled Nd:YAG laser treatment.  Urology. 2003;  61 1011-1015
    Search in Google Scholar
  • 56 Wang X L, Wang H W, Wang H S, Xu S Z, Liao K H, Hillemanns P. Topical 5-aminolaevulinic acid-photodynamic therapy for the treatment of urethral condylomata acuminata.  Br J Dermatol. 2004;  151 880-885
    Search in Google Scholar
  • 57 Popken G, Wetterauer U, Schultze-Seemann W. Kidney-preserving tumor resection in renal cell carcinoma with photodynamic detection by 5-aminolaevulinic acid: preclinical and preliminary clinical results.  BJU Int. 1999;  83 578-582
    Search in Google Scholar
  • 58 Frimberger D, Schneede P, Hungerhuber E. et al . Autofluorescence and 5-aminolevulinic acid induced fluorescence diagnosis of penile carcinoma - new techniques to monitor Nd:YAG laser therapy.  Urol Res. 2002;  30 295-300
    Search in Google Scholar
  • 59 Pinthus J H, Bogaards A, Weersink R, Wilson B C, Trachtenberg J. Photodynamic therapy for urological malignancies: past to current approaches.  J Urol. 2006;  175 1201-1207
    Search in Google Scholar
  • 60 Zaak D, Sroka R, Höppner M. et al . Photodynamic therapy by means of 5-ALA induced PPIX in human prostate cancer - Preliminary results.  Medical Laser Application. 2003;  18 91-95
    Search in Google Scholar
  • 61 Zaak D, Sroka R, Stocker S. et al . Photodynamic therapy of prostate cancer by means of 5-aminolevulinic acid-induced protoporphyrin IX - In vivo experiments on the Dunning rat tumor model.  Urologia Internationalis. 2004;  72 196-202
    Search in Google Scholar
  • 62 Moore C M, Nathan T R, Lees W R. et al . Photodynamic therapy using meso tetra hydroxy phenyl chlorin (mTHPC) in early prostate cancer.  Lasers Surg Med. 2006;  38 356-363
    Search in Google Scholar
  • 63 Weersink R A, Bogaards A, Gertner M. et al . Techniques for delivery and monitoring of TOOKAD (WST09)-mediated photodynamic therapy of the prostate: clinical experience and practicalities.  J Photochem Photobiol B. 2005;  79 211-222
    Search in Google Scholar
  • 64 Verigos K, Stripp D C, Mick R. et al . Updated results of a phase I trial of motexafin lutetium-mediated interstitial photodynamic therapy in patients with locally recurrent prostate cancer.  J Environ Pathol Toxicol Oncol. 2006;  25 373-387
    Search in Google Scholar
  • 65 Zhou X, Pogue B W, Chen B. et al . Pretreatment photosensitizer dosimetry reduces variation in tumor response.  Int J Radiat Oncol Biol Phys. 2006;  64 1211-1220
    Search in Google Scholar
  • 66 Jankun J, Keck R W, Skrzypczak-Jankun E, Lilge L, Selman S H. Diverse optical characteristic of the prostate and light delivery system: implications for computer modelling of prostatic photodynamic therapy.  BJU Int. 2005;  95 1237-1244
    Search in Google Scholar
  • 67 Yu G, Durduran T, Zhou C. et al . Real-time in situ monitoring of human prostate photodynamic therapy with diffuse light.  Photochem Photobiol. 2006;  82 1279-1284
    Search in Google Scholar
  • 68 Thompson M S, Johansson A, Johansson T. et al . Clinical system for interstitial photodynamic therapy with combined on-line dosimetry measurements.  Appl Opt. 2005;  44 4023-4031
    Search in Google Scholar
  • 69 Schmidbauer J, Witjes F, Schmeller N, Donat R, Susani M, Marberger M. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy.  J Urol. 2004;  171 135-138
    Search in Google Scholar
  • 70 Lopatkin N A, Kamalov A A, Kudriavtsev I, Tokarev F V. [Fluorescent diagnostics of urinary bladder cancer].  Urologiia. 2000;  4 3-6
    Search in Google Scholar
  • 71 Koenig F, McGovern F J, Larne R, Enquist H, Schomacker K T, Deutsch T F. Diagnosis of bladder carcinoma using protoporphyrin IX fluorescence induced by 5-aminolaevulinic acid.  BJU Int. 1999;  83 129-135
    Search in Google Scholar
  • 72 Riedl C R, Plas E, Pfluger H. Fluorescence detection of bladder tumors with 5-amino-levulinic acid.  J Endourol. 1999;  13 755-759
    Search in Google Scholar
  • 73 Filbeck T, Roessler W, Knuechel R, Straub M, Kiel H J, Wieland W F. Clinical results of the transurethreal resection and evaluation of superficial bladder carcinomas by means of fluorescence diagnosis after intravesical instillation of 5-aminolevulinic acid.  J Endourol. 1999;  13 117-121
    Search in Google Scholar
  • 74 Kriegmair M, Baumgartner R, Knüchel R, Stepp H, Hofstaedter F, Hofstetter A. Detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence.  J Urol. 1996;  155 105-110
    Search in Google Scholar
  • 75 Sim H G, Lau W K, Olivo M, Tan P H, Cheng C W. Is photodynamic diagnosis using hypericin better than white-light cystoscopy for detecting superficial bladder carcinoma?.  BJU Int. 2005;  95 1215-1218
    Search in Google Scholar
  • 76 D'Hallewin M A, Bezdetnaya L, Guillemin F. Fluorescence detection of bladder cancer: a review.  Eur Urol. 2002;  42 417-425
    Search in Google Scholar
  • 77 D'Hallewin M A, De Witte P A, Waelkens E, Merlevede W, Baert L. Fluorescence detection of flat bladder carcinoma in situ after intravesical instillation of hypericin.  J Urol. 2000;  164 349-351
    Search in Google Scholar
  • 78 Kriegmair M, Baumgartner R, Lumper W. et al . Early clinical experience with 5-aminolevulinic acid for the photodynamic therapy of superficial bladder cancer.  Br J Urol. 1996;  77 667-671
    Search in Google Scholar
  • 79 Berger A P, Steiner H, Stenzl A, Akkad T, Bartsch G, Holtl L. Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study.  Urology. 2003;  61 338-341
    Search in Google Scholar

Dr. rer. biol. hum. Herbert Stepp

Laser-Forschungslabor am LIFE-Zentrum, Klinikum der Universität München-Großhadern

Marchioninistr. 23

81377 München

Phone: 089/70954880

Fax: 089/70954864

Email: herbert.stepp@med.uni-muenchen.de