Intraoperative photodynamic therapy of bladder cancer with alasens (results of multicenter trial)

The results of multicenter prospective trial for efficacy of combined modality treatment: transurethral resection (TUR) + photodynamic therapy (PDT) with alasens for bladder cancer are represented in the article. Trials were organized by Research Institute of Organic Intermediates and Dyes and conducted according to clinical protocol approved by Ministry of Health of Russia, at the sites of leading Russian cancer clinical centers. The trial included 45 subjects with verified diagnosis of non-muscle-invasive bladder cancer. Patients underwent TUR of bladder with simultaneous PDT as anti-relapse treatment. Alasens was administered to patients as intravesicular instillation of 3% solution in volume of 50 ml with 1.5–2h exposure (prior to TUR). TUR was performed after instillation. PDT session was conducted immediately after the completion of TUR on a single occasion by means of combined local irradiation on tumor bed with diffuse irradiation on whole urinary bladder mucosa (light dose of local irradiation – 100 J/cm2, diffuse irradiation – 20 J/cm²). Good tolerance of the treatment was noticed, there were no complications. Among 45 patients included in the trial, 35 (78%) completed 12 month protocol follow-up without relapse. The recurrence of bladder tumor was registered in 10 (22%) cases 6–12 months after TUR+PDT including 3 patients with recurrence 6 months after treatment, 3–9 months and 4–12 months. These patients underwent repeated TUR, whereafter their follow-up in the settings of the clinical trial was disposed. Thus, PDT with alasens after TUR allowed to decrease the recurrence rate of non-muscle-invasive bladder cancer for 1st year after treatment to 22% versus 40–80% for TUR as monotherapy according to literature data. The obtained results were comparable by efficiency with TUR combined with methods of adjuvant treatment for bladder tumors (the recurrence rates for 1-year follow-up after TUR+chemotherapy – 36–44%, after TUR+BCG – 20–59%).

1. Zlokachestvennye novoobrazovaniya v Rossii v 2011 godu (zabolevaemost' i smertnost') (Malignant neoplasms in Russia in 2011 (incidence and mortality)), pod red. V.I.Chissova, V.V. Starinskogo, G.V. Petrovoi, M.: FGBU «MNIOI im. P.A. Gertsena» Minzdrava Rossii, 2013, pp. 1–288.

2. Grigor'ev E.G., Frolova I.G., Usynin E.A., Velichko S.A., Okunev V.V. Rak mochevogo puzyrya: vozmozhnosti luchevykh metodov diagnostiki (obzor literatury) (Bladder cancer: role of diagnostic imaging techniques (literature review)), Sibirskii onkologicheskii zhurnal, 2013, № 3 (57), pp. 75–81.

3. Apolikhin O.I., Sivkov A.V., Beshliev D.A. Analiz uronefrologicheskoi zabolevaemosti v RF po dannym ofitsial'noi statistiki (Analysis of urological morbidity in the Russian Federation according to official statistics), Eksperimental'naya i klinicheskaya urologiya, 2010, № 1, pp. 4–11.

4. Vorob'ev A.V. Klassifikatsiya i diagnostika raka mochevogo puzyrya, voprosy differentsial'noi diagnostiki (Classification and diagnosis of bladder cancer, issues of differential diagnosis), Prakticheskaya onkologiya, 2003, T. 4, № 4, pp. 196–203.

5. Al'-Shukri S.K., Tkachuk V.N. Opukholi mochepolovykh organov: rukovodstvo dlya vrachei (Urogenital tumors: manual for physicians), SPb.: Piter, 2000, pp. 1–320.

6. Matveev B.P. Rak mochevogo puzyrya (Bludder cancer), M.: Verdana, 2003, pp. 1–406.

7. Pereverzev A.S., Petrov S.B. Opukholi mochevogo puzyrya (Bludder tumors), Khar'kov: Fakt, 2002, pp. 1–303.

8. Rusakov I.G., Bystrov A.A. Khirurgicheskoe lechenie, khimioi immunoterapiya bol'nykh poverkhnostnym rakom mochevogo puzyrya (Surgical treatment chemo- and immunotherapy of pathients with bladder cancer), Prakticheskaya onkologiya, 2003, № 4, pp. 214–24.

9. Hall R.R. The role of transurethral surgery alone and with combined modality therapy. In: N.J. Vogelzang, P.T. Scardino, W.U. Shipley et al. Comprehensive textbook of genitourinary oncology, Baltimore: William & Wilkins, 1996, pp. 509–13.

10. Zubkov A.Yu., Nuriev I.R., Sitdykov E.N. Rol' ad"yuvantnoi vnutripuzyrnoi khimioterapii v kombinirovannom organosokhranyayushchem lechenii nemyshechno-invazivnogo raka mochevogo puzyrya (Role of adjuvant intravesical chemotherapy in the combined organ-sparing treatment of non-muscle-invasive bladder cancer), Onkourologiya, 2014, № 2, pp. 26–8.

11. Ali-el-dein B. et. al. Intravesical epirubicin versus doxorubicin for superficial bladder tumors (stages pTa and pT1): a randomized prospective study, J. Urol., 1997, Vol. 158 (1), pp. 68–74.

12. Buffioux С. et al. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of two European Organization for Research and Treatment of Cancer randomized trials with mitomycin С and doxorubicin comparing early versus delayed instillations and short term versus long term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group, J Urоl, 1995, Vol. 153, pp. 934–41.

13. Krege S. et al. A randomized multicenter trial of adjuvant therapy in superficial bladder cancer: transurethral resection only versus transurethral resection plus mitomycin С versus transurethral resection plus bacillus Calmette-Guerin. Participating Clinic, J. Urol., 1996, Vol. 156. pp. 962–966.

14. Melekos M.D. et al. Intravesical instillations of 4-epidoxorubicin (epirubicin) in the prophylactic treatment of superficial bladder cancer: results of controlled prospective study, J. Urol., 1992, Vol. 147, P. 371–75.

15. Zein Т.А. et al. Bone marrow suppression after intravesical mitomycin С treatment, J. Urol., 1986, Vol.136, pp. 459–60.

16. Wittes R. et al. Severe bacillus Calmelle-Guerin cystitis responds to systemic steroids when and tuberculous drugs and local steroids fail, J. Urol., 1999, Vol. 161, pp. 1568–9.

17. Machinskaya E.A., Ivanova-Radkevich V.I. Obzor mekhanizmov selektivnogo nakopleniya fotosensibilizatorov razlichnoi khimicheskoi struktury v opukholevoi tkani (Review of selective accumulation of photosensitizers with different chemical structure in tumor tissue), Fotodinamicheskaya terapiya i fotodiagnostika, 2013, № 4, pp. 19–23.

18. Filonenko E.V. Flyuorestsentnaya diagnostika i fotodinamicheskaya terapiya – obosnovanie primeneniya i vozmozhnosti v onkologii (Fluorescence diagnostics and photodynamic therapy: justification of applications and opportunities in oncoligy), Fotodinamicheskaya terapiya i fotodiagnostika, 2014, № 1, pp. 3–7.

19. Peretrukhin A.A., Gyulov Kh.Ya.K.P.A., Zolotykh M.A., Abramov I.I., Kudryashov G.Yu. Fotodinaicheskaya terapiya v lechenii poverkhnostnogo raka mochevogo puzyrya (Photodynamic therapy in the treatment of superficial bladder cancer), Fotodinamicheskaya terapiya i fotodiagnostika, 2014, № 1, pp. 37–38.

20. Stranadko E.F. Istoricheskii ocherk razvitiya fotodinamicheskoi terapii: obzor (Historical sketch of development of photodynamic therapy: review), Lazernaya meditsina, 2002, T. 6, № 1, pp. 4–8.

21. Mironov A.F. Fotodinamicheskaya terapiya raka – novyi effektivnyi metod diagnostiki i lecheniya zlokachestvennykh opukholei (Photodynamic therapy of cancer – a new effective method of diagnosis and treatment of malignant tumors), Sorovskii obrazovatel'nyi zhurnal, 1996, № 8, pp. 32–40.

22. Nseyo U.O., DeHaven J., Dougherty T.J., Potter W.R., Merrill D.L., Lundahl S.L., Lamm D.L. Photodynamic therapy (PDT) in the treatment of patients with resistant superficial bladder cancer: a long-term experience, J. Clin. Laser Med. Surg., 1998, Vol. 16 (1), pp. 61–8.

23. Uchibayashi T., Koshida K., Kunimi K., Hisazumi H. Whole bladder wall photodynamic therapy for refractory carcinoma in situ of the bladder, Br. J. Cancer, 1995, Vol. 71 (3), pp. 625–8.

24. Stenzi A., Eder I., Kostron H., Klocker H., Bartsch G. Electromotive diffusion (EMD) and photodynamic therapy with delta-aminolaevunic acid (delta-ALA) for superficial bladder cancer, J. Photochem. Photobiol. B., 1996, Vol. 36 (2), pp. 233–6.

25. Berger A.P. et al. Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study, Urology, 2003, Vol. 61 (2), pp. 338–41.

26. Schenkman E., Lamm D.L. Superficial bladder cancer therapy, Scientific World Journal, 2004, Vol. 28, № 4, Suppl. 1, pp. 387–99.

27. Loshchenov V.B., Lin'kov K.G., Savel'eva T.A., Loshchenov M.V., Model' S.S., Borodkin A.V. Apparaturnoe i instrumental'noe obespechenie flyuorestsentnoi diagnostiki i fotodinamicheskoi terapii (Hardware and tool equipment for fluoreacence diagnostics and photodynamic therapy), Fotodinamicheskaya terapiya i fotodiagnostika, 2013, № 3, pp. 17–23.

28.