Bladder CancerPhotodynamic Diagnosis (5-Aminolevulinic Acid) of Transitional Cell Carcinoma After Bacillus Calmette-Guérin Immunotherapy and Mitomycin C Intravesical Therapy
Introduction
Photodynamic diagnosis (PDD) enhances bladder tumor detection during cystoscopy by instilling the bladder with a photosensitive dye such as 5-aminolevulinic acid (5-ALA) or hexaminolevulinic acid (HAL). δ-Aminolevulinic acid is a precursor in the heme biosynthesis pathway and leads to the predominant accumulation of endogenous protoporphyrin IX (PpIX) in malignant cells. After illumination with violet-blue light, PpIX shows red fluorescence in contrast to the blue reflection of normal bladder tissue [1].
Fluorescence cystoscopy improves the detection of occult bladder tumors, especially carcinoma in situ. The overall sensitivity of fluorescence cystoscopy is 97%, compared with 76% of white-light endoscopy (WLE). However, the specificity of 5-ALA–induced PDD is merely 50% [2], [3]. False fluorescence is associated with the female gender (in print) [4], recent transurethral resection of bladder tumors (TURBT) [4], [5], previous intravesical therapy (IVT) [6], inflammation [7], and tangential illumination of the bladder wall with blue light that generally results in fluorescence of the trigone, bladder neck, and anterior bladder wall [7].
Bacillus Calmette-Guérin (BCG) instillation induces inflammation of the bladder wall with chemotaxis and infiltration of neutrophils, monocytes/macrophages, and lymphocytes. Activation of the innate immunity induces and supports antitumor mechanisms [8]. It is assumed that BCG-induced inflammation causes false-positive fluorescence in PDD, but this has not yet been proven. Mitomycin C (MMC) is an antibiotic antitumor agent that exerts its anticellular activity by inhibiting DNA synthesis primarily by inducing DNA cross-linking [9]. The specificity of PDD of bladder cancer may be improved if the time-dependent influence of IVT on false-positive rates is demonstrated and PDD is postponed after a recent IVT.
The objective of this study was to investigate the influence of BCG and MMC on false positives in PDD, and to determine the optimal waiting period after IVT to minimize the number of false positives in a subsequent PDD. A secondary objective was to investigate whether leukocyturia could be related to IVT-induced inflammation.
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Patients
Between November 1998 and January 2008, data of 306 patients, 552 PDD procedures, and 1874 biopsies were prospectively collected (Table 1). About 2 h before the PDD procedure, patients were instilled with a solution of 1.5 g 5-ALA (Medac GmbH, Hamburg, Germany) in 50 ml 1.4% sodium bicarbonate using a 10-F catheter, to induce fluorescence. In total, 151 patients had undergone IVT with BCG, MMC, epirubicin, or other chemotherapy (ie, 239 procedures) (Table 1). Patients did not receive one immediate
Results
Photodynamic diagnosis resulted in the resection of 1208 fluorescent-positive lesions, of which 542 (45%) were false positive. Fluorescence cystoscopy led to the identification of 96% of the 692 tumors. The sensitivity and specificity of WLE and PDD are 73% and 75%, 96% and 45%, respectively. The PDD specificity of primary patients, patients with a first, second, third, fourth, and fifth PDD procedure, are 52%, 47%, 44%, 41%, 38%, and 33%, respectively.
Table 1 shows the patients’
Discussion
This study shows that BCG is associated with an increase in urinary leukocyte concentrations, bladder inflammation, and false positives in PDD. The specificity of PDD decreased up to 3 mo after the last BCG instillation (Fig. 1).
Grimbergen et al have previously reported that IVT <6 mo results in a significantly higher false-positive rate compared with IVT >6 mo before fluorescence cystoscopy, 39.6% and 30.6%, respectively [6]. We now demonstrate that BCG instillations are responsible for these
Conclusions
More than one BCG instillation within 3 mo before fluorescence cystoscopy decreases the specificity of PDD. The false positives in PDD should be weighed against the increase in detection rate. For future studies, it would be worthwhile to study the cost effectiveness of PDD in patients with multiple recurrences, especially in patients with recurrent Ta tumors.
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