Adult Urology 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 Stefan Denzinger, Maximilian Burger, Bernhard Walter, Ruth Knuechel, Wolfgang Roessler, Wolf F. Wieland, and Thomas Filbeck OBJECTIVES Several studies have shown that 5-aminolevulinic acid (5-ALA)-induced fluorescence cystos- copy improves the detection of superficial bladder cancer. The results have suggested a reduced rate of recurrent tumors with the use of 5-ALA fluorescence before bladder tumor resection. We performed a prospective, randomized trial to investigate whether the long-term tumor recurrence and residual tumor rates can be decreased using 5-ALA fluorescence diagnosis (FD). METHODS A total of 301 patients with suspected superficial bladder carcinoma were randomized to transurethral resection (TUR) using conventional white light (WL) or FD. TUR was repeated to evaluate the residual tumor rate. In addition, patients were followed up for a median of 83 (WL) and 86 (FD) months to evaluate recurrence-free survival (RFS). RESULTS Of the 301 patients, 191 were available for the efficacy analysis. The residual tumor rate was 25.2% in the WL arm versus 4.5% in the FD arm (P 0.0001). The RFS rate after 2, 4, 6, and 8 years was 73%, 64%, 54%, and 45% in the WL group and 88%, 84%, 79%, and 71% in the FD group, respectively, revealing a statistically significant difference in favor of fluorescent TUR (P = 0.0003). CONCLUSIONS 5-ALA-induced FD is significantly superior statistically to conventional WL TUR with respect to the residual tumor rate and RFS. This advantage of decreased bladder tumor recurrence risk was maintained with high statistical significance for at least 8 years. The differences in RFS imply that FD offers a clinically relevant procedure to reduce the incidence of tumor recurrence. UROLOGY 69: 675– 679, 2007. © 2007 Elsevier Inc. F ive-aminolevulinic acid (5-ALA)-induced fluores- cence diagnosis (FD) facilitates the detection of flat lesions in the bladder that are poorly visible under conventional white light (WL). The recurrence of blad- der cancer is related to hidden malignant and premalig- nant lesions. 1–4 The detection of small papillary and flat urothelial lesions has significantly improved with the introduction of FD with 5-ALA. Biopsy-related studies using 5-ALA have usually been presented to illustrate the diagnostic reliability of this method. In prospective stud- ies, this procedure has had a sensitivity of more than 97% and a specificity of 35% to 70%. 5–8 Thus, decreases in the residual tumor and recurrence rates have been suggested. Overall, biopsy-related studies have given no indication of the extent of the clinical benefit. We performed a single-institution, randomized, prospective, comparative Phase III study to investigate the effect of FD on the recurrence-free interval. We previously reported the ini- tial study results with a median patient follow-up of 21 months. 9 With a median follow-up of 84 months, this is the first assessment of the clinical long-term benefit of 5-ALA-induced FD. MATERIAL AND METHODS Our institution provided ethical approval, and all patients pro- vided written informed consent. From 1997 to 2000, 301 pa- tients with endoscopically suspected bladder cancer were ran- domized to two study arms. Patients with recurring bladder cancer had to have been disease free for a minimum of 12 months. All patients underwent transurethral resection (TUR). The 150 patients in the first arm underwent TUR of the bladder From the Department of Urology, University of Regensburg, Regensburg, Germany; and Institute of Pathology, University Hospital, RWTH Aachen, Germany Reprint requests: Stefan Denzinger, M.D., Department of Urology, University of Regensburg, Landshuter Strasse 65, Regensburg D-93053, Germany. E-mail: stefandenzinger@hotmail.com Submitted: June 19, 2006; accepted (with revisions): December 14, 2006 © 2007 Elsevier Inc. 0090-4295/07/$32.00 675 All Rights Reserved doi:10.1016/j.urology.2006.12.023