Eleanor Ray

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 Lairds 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.

Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial).

BACKGROUND Standard treatment for upper urinary tract urothelial carcinoma (UUTUC) is nephroureterectomy. Subsequently, around 40% of patients will develop a bladder tumour potentially because of implantation from the primary tumour. OBJECTIVE To prevent bladder tumour after nephroureterectomy with a single postoperative dose of intravesical mitomycin C (MMC). DESIGN, SETTING, AND PARTICIPANTS A prospective, randomised, nonblinded trial (ODMIT-C: One Dose Mitomycin C) was undertaken in 46 British centres between July 2000 and December 2006. The study recruited 284 patients with no previous or concurrent history of bladder cancer undergoing nephroureterectomy for suspected UUTUC. INTERVENTION A single postoperative intravesical dose of MMC (40 mg in 40 ml saline) or standard management on removal of the urinary catheter. MEASUREMENTS Bladder tumour formation was judged by visual appearance at cystoscopy at 3, 6, and 12 mo following nephroureterectomy. RESULTS AND LIMITATIONS One hundred forty-four patients were randomised to receive MMC and 140 patients to receive standard care. In the MMC arm, 105 of 144 patients (73%) and 115 of 140 patients (82%) in the standard care arm received their allocated treatment. Thirteen of 105 patients who received MMC and 20 of 115 patients allocated to standard treatment did not complete follow-up. By modified intention-to-treat analysis, 21 of 120 patients (17%) in the MMC arm developed a bladder recurrence in the first year compared to 32 of 119 patients (27%) in the standard treatment arm (p=0.055). By treatment as per protocol analysis, 17 of 105 patients (16%) in the MMC arm and 31 of 115 patients (27%) in the standard treatment arm developed a recurrence (p=0.03). No serious adverse events were reported. A limitation is that histologic proof of recurrence was not required in this trial. CONCLUSIONS A single postoperative dose of intravesical MMC appears to reduce the risk of a bladder tumour within the first year following nephroureterectomy for UUTUC. The absolute reduction in risk is 11%, the relative reduction in risk is 40%, and the number needed to treat to prevent one bladder tumour is nine.

Bladder cancer: new TUR techniques

Transurethral resection of bladder tumours (TURBT) using a wire loop remains the gold-standard treatment for bladder tumours, but it is associated with unacceptably high early recurrence rates after first resection. Improvements to standard resection techniques and a range of optical and technological advances offer exciting possibilities for improving outcomes. Early second resection has been shown to reduce recurrence rates, and increase response to intravesical chemotherapy and/or immunotherapy. It should be considered in most high-risk non-muscle invasive cancers (T1; G3; multifocal) being managed by bladder conservation. Newer energy sources, such as laser, may facilitate day case management of bladder tumours using local anaesthesia in select groups of patients. The novel technique of photodynamic diagnosis improves tumour detection, and quality of resection, and is likely to become the standard for initial tumour management. The traditional ‘incise and scatter’ resection technique goes against all oncological surgical principles. En-bloc resection of tumours would be far preferable and demands further development and evaluation. The technique of TURBT needs to evolve to allow first-time clearance of disease and low recurrence rates.

Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette‐Guérin

Study Type – Diagnosis (case series) Level of Evidence 4

Hexylaminolaevulinate ‘blue light’ fluorescence cystoscopy in the investigation of clinically unconfirmed positive urine cytology

To investigate the value of photodynamic diagnosis (PDD) using hexylaminolaevulinate (Hexvix®, PhotoCure, Oslo, Norway) in the investigation of patients with positive urine cytology who have no evidence of disease after standard initial investigations.

Open partial nephrectomy: outcomes from two UK centres

To define the current achievable outcomes from open partial nephrectomy (OPN) in the UK at a time when other treatments for small kidney tumours are increasingly being advocated. Current knowledge of the effectiveness of OPN is limited by the fact that published data are almost exclusively derived from a very few centres of established world renown.

Hexylaminolevulinate Photodynamic Diagnosis for Multifocal Recurrent Nonmuscle Invasive Bladder Cancer

OBJECTIVE To determine the potential for hexylaminolevulinate (HAL) photodynamic diagnosis (PDD) to improve the management of multifocal recurrent nonmuscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS Patients with a history of NMIBC and with at least two suspected papillary recurrences were enrolled in this prospective study between April 2005 and October 2006. The photosensitizer was hexylaminolevulinate (HAL) (PhotoCure, Norway), and the Storz D-light system was used to detect fluorescence. The bladder was mapped initially under white light and then using HAL-photodynamic diagnosis (PDD). The number and types of additional lesions detected by HAL-PDD over white light cystoscopy were measured. RESULTS Eighteen patients (11 men), median age 74 years (range 35-84 yrs), underwent HAL-PDD. The median HAL instillation time was 109 minutes (range 60-250 min). Recurrent bladder cancer was confirmed histologically in 14/18 (78%) patients. Additional pathology was detected in 8/14 (57%) patients with confirmed recurrence and confirmed histologically in 6 of these. Additional pathology was papillary in 5/6 (83%) patients, and flat pathology was found in all six patients with additional foci. Carcinoma in situ (CIS) was detected in 4/6 (67%) patients with additional foci, three of whom were subsequently treated with intravesical bacille Calmette-Guérin (BCG). The sensitivity of HAL-PDD for the detection of tumor was 97.8%, compared with 69.6% for white light cystoscopy. The false-positive fluorescence-guided biopsy rate was 18/63 (29%). CONCLUSION HAL-PDD allows more complete management of bladder tumor in patients with multifocal recurrence. The high frequency of additional lesions detected and the rate of detection of CIS suggest that HAL-PDD should be the standard of care.

SHOULD UROLOGISTS BE SPENDING MORE TIME ON THE GOLF COURSE

An unshakeable principle of the surgical treatment of cancer is to dissect through normal tissue and to remove the tumour with a negative margin. Conventional wire-loop transurethral resection of bladder tumour (TURBT) does not achieve this. The tumour is deliberately incised and removed piecemeal, scattering millions of tumour cells throughout the bladder. In any other tumour type this would be considered oncological madness; in the bladder it is the norm. Perhaps unsurprisingly, recurrence rates for superficial bladder cancer are astronomically high, at up to 64% at 5 years. In other tumour types this rate of recurrence would be unacceptable: local recurrence after partial nephrectomy for renal cancer is 5–10% at 5 years; after breast conservation therapy it is 5–22%. Moreover, in rectal cancer surgery, operative technique has been shown to be a very important factor of local recurrence rates: after total mesorectal excision there is recurrence in 4–9%, compared with 32–35% with conventional surgery [1]. The question inevitably arises as to whether the technique of wire-loop TURBT is outdated. In particular, might a technique that attempts to remove a bladder cancer en bloc by dissecting through normal tissue be more oncologically appropriate? Could urologists take their cue from golfers; the perfect bunker shot is made by swinging the sand wedge through the sand under the ball with no contact between the club and the ball. The ball emerges from the bunker on a cushion of sand, to float gently onto the green (Fig. 1). Should we be looking to execute a ‘sand wedge resection’ of bladder tumours?

Exploring the potential of immunohistochemistry to identify renal oncocytoma

Objective: To determine the potential for a novel immunohistochemistry panel to accurately distinguish oncocytoma from other renal tumour subtypes. Material and methods: Forty renal tumours removed by surgery between 2000 and 2006 in a single tertiary referral centre in the UK were studied retrospectively. Paraffin blocks from 10 each of oncocytoma, papillary RCC, clear cell RCC and chromophobe RCC were examined. The tumours were tested using a panel of antibodies comprising CK7, CK18, CD15, N-cadherin, E-cadherin and EpCAM. The primary outcome measure was the number of each tumour type staining positively with each marker. The immunohistochemistry marker was considered to be positive if more than 10% of the tumour cells stained positively. No staining or focal staining (<10% of the tumour cells) was considered a negative test. Results: CK7, CD15 and EpCAM were able to distinguish between renal oncocytoma and chromophobe RCC: no oncocytoma stained with either CK7 or EpCAM, however 7/10 (70%) stained positive for CD15. Conversely, 8/10 (80%) chromophobe RCC stained positive with CK7 and EpCAM but none stained for CD15. Conclusions: In this preliminary study the immunohistochemistry panel shows promise in differentiating between renal oncocytoma and chromophobe RCC. The panel deserves prospective evaluation on needle biopsy specimens.

MP22-08 LONG TERM FOLLOW UP OF A PROSPECTIVE RANDOMISED TRIAL OF HEXYLAMINOLEVULINATE (HEXVIX®) PHOTODYNAMIC DIAGNOSIS (PDD) ASSISTED VERSUS CONVENTIONAL WHITE-LIGHT TRANSURETHRAL RESECTION (TURBT) IN NEWLY PRESENTING NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC)

INTRODUCTION AND OBJECTIVES: Despite Hexvix PDD improving the detection of bladder tumours, in a prospective randomized trial in newly presenting bladder tumours we were unable to demonstrate reduced recurrence in the first year post resection. We now report longer-term follow-up with 3-year recurrence and progression rates from the trial. METHODS: 249 patients with newly presenting suspected NMIBC were enrolled at our institution between March 2005 and April 2010, and randomized to receive either Hexvix PDD assisted TURBT plus single shot Mitomycin C or white-light (W/L) TURBT plus single shot Mitomycin C. Patients with muscle invasive bladder cancer, or a previous history of bladder cancer were excluded. All operations were performed by 3 specialized bladder cancer teams. Subsequent management was standardized for all patients. All data was prospectively collected. RESULTS: 129 patients received Hexvix PDD assisted TURBT and 120 patients received W/L TURBT. 185 of 249 patients were found to have NMIBC (Hexvix e 97, W/L e 88). Final TNM classification was low grade/G1pTa 1⁄4 98 (Hexvix e 50, W/L 48); high grade/G3pTa 1⁄4 28 (Hexvix e 13, W/L 15); high grade/G3pT1 1⁄4 57 (Hexvix e 35, W/L 22). Primary CIS was seen in one patient and secondary CIS in 37 (Hexvix e 25, W/L 12). Of the patients who completed 3-month follow up, 17/86 (20%) in the Hexvix group and 14/82 (17%) in the W/L group had a recurrence (p 1⁄4 0.70). Of the patients who were recurrence free at 3 months and completed 1 year follow up, 10/63 (16%) in the Hexvix group and 15/67 (22%) in the W/L group had a recurrence (p1⁄40.38). Of the patients who were recurrence free at 1 year and completed 3 year follow up, 5/47 (10.6%) in the Hexvix group and 7/46 (15.2%) in the W/L group had a recurrence (p1⁄40.51). 3/97 (3.1%) in the Hexvix group and 4/88 (4.5%) in the W/L group had progressed to muscle invasive disease at 3 years (p1⁄40.61). (Table 1) CONCLUSIONS: Despite improving the accuracy of bladder cancer diagnosis, Hexvix PDD has not been shown in this trial to reduce the recurrence rate or progression rate of NMIBC at 3 years’ follow-up.