Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data.

BACKGROUND: Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. OBJECTIVE: To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. DESIGN, SETTING, AND PARTICIPANTS: This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non-muscle-invasive bladder cancer (NMIBC). INTERVENTION: A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We studied the detection of NMIBC (intention to treat [ITT]: n=831; six studies) and recurrence (per protocol: n=634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. RESULTS AND LIMITATIONS: BL cystoscopy detected significantly more Ta tumours (14.7%; p<0.001; odds ratio [OR]: 4.898; 95% CI, 1.937-12.390) and CIS lesions (40.8%; p<0.001; OR: 12.372; 95% CI, 6.343-24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p<0.001), significant also in patients with primary (20.7%; p<0.001) and recurrent cancer (27.7%; p<0.001), and in patients at high risk (27.0%; p<0.001) and intermediate risk (35.7%; p=0.004). In 26.7% of patients, CIS was detected only by BL (p<0.001) and was also significant in patients with primary (28.0%; p<0.001) and recurrent cancer (25.0%; p<0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p=0.006; RR: 0.761 [0.627-0.924]), and lower in patients with T1 or CIS (p=0.052; RR: 0.696 [0.482-1.003]), Ta (p=0.040; RR: 0.804 [0.653-0.991]), and in high-risk (p=0.050) and low-risk (p=0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. CONCLUSIONS: This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

A chemosensitivity test for superficial bladder cancer based on three-dimensional culture of tumour spheroids.

OBJECTIVES: Three-dimensional (3D) spheroids are a good model for studying in vitro chemosensitivity because they reproduce unicellular and multicellular mechanisms of drug resistance. We aimed to develop a chemosensitivity test for intravesical drugs and to also verify the effects of verapamil (VPM) and ciprofloxacin (CIPRO). METHODS: Cold cup biopsies from 40 superficial bladder tumours were taken, fragmented, and left in culture. 3D-spheroids were obtained and transferred into a 24 multiwell dish containing (1) wells 1-3: 1 mg/ml epirubicin (EPI); (2) 4-6: 1 mg/ml EPI+0.5 mg/ml VPM; (3) 7-9: 1 mg/ml adriamycin (ADR); (4) 10-12: 1 mg/ml thiotepa (THIO); (5) 13-15: 1 mg/ml mitomycin C (MMC); (6) 16-18: 1mg/ml EPI+0.2 mg/ml CIPRO; (7) 19-21: 0.2 mg/ml CIPRO; (8) 22-24: controls. Sensitivity was calculated by using the trypan blue assay. RESULTS: Evaluability of clinically relevant tests (G1-G2 lesions) was 84% (21 of 25 patients). MMC was the best agent (p<0.001) with mean sensitivity being 50%, followed by THIO (37%), EPI (7%), and ADR (3%). We found no significant difference (p=0.370) between CIPRO and the control, or between EPI+CIPRO and EPI alone (p=0.550). VPM markedly enhanced sensitivity to EPI compared with EPI alone (97% vs. 7%, p<0.001). CONCLUSIONS: Our assay allows determining sensitivity to several drugs in superficial bladder tumours. It might be used in clinical practice to select the best drug for each patient. It also has experimental utility in investigating the effect of new drugs or combinations. VPM reverted resistance to EPI. CIPRO showed no effect on bladder tumour spheroids.