Bladder cancer (BC) is a frequently common disease with the highest lifetime treatment costs per patient of all cancers Citation[1]. With an estimated 70,980 new diagnoses of BC and approximately 14,330 BC-related deaths in 2009, the burden to the patients and healthcare systems is expected to continue to rise Citation[2]. The high rate of recurrence and progression of BC requires vigilant endoscopic exams. Frequent surgical interventions and re-interventions contribute approximately two-thirds of the overall expenses Citation[3]. The European Association of Urology (EAU) and the American Urological Association (AUA) recommend urinary cytology and cysto-urethroscopy as diagnostic standard of care Citation[4–6]. In addition, traditional imaging (ultrasonography, excretory urography and computer tomography) can be utilized to detect simultaneous upper urinary tract tumors; this is now questioned owing to the low incidence of significant findings and poor detection of small papillary tumors, especially carcinoma in situ (CIS).
Although novel diagnostic tools, such as urine markers, support BC detection at an earlier stage, they cannot replace the current diagnostic standard. Until now, white-light cystoscopy (WLC) with transurethral resection of the bladder (TURBT) has been the gold standard in BC diagnosis Citation[4,6]. TURBT is also the recommended initial treatment for bladder tumors according to EAU guidelines, followed by one immediate instillation of intravesical chemotherapy Citation[4,6]. Urinary cytology as the second recommended diagnostic mainstay has several limitations owing to its low sensitivity (particularly in the detection of low-grade BC) and its poor reproducibility. While larger papillary lesions can be detected in WLC, it has its limitations in the identification of small tumors and patients with flat CIS lesions. CIS in particular has a high risk of progression Citation[7]. Owing to deficient visualization of bladder tumors and their extensions during TURBT, many studies have reported that residual tumor masses are often detected at a second resection Citation[8]. The initial diagnosis, however, dictates the clinical course, and this underscores the value of new techniques that have been developed to enhance tumor detection and resection at the primary intervention.
Photodynamic diagnosis
Photodynamic diagnosis (PDD) is an emerging technology with the potential for improving the effectiveness of cystoscopy and TURBT. PDD is recommended by the EAU and has advanced the detection of papillary and flat bladder lesions compared with WLC in numerous clinical studies Citation[4,6]. PDD is an optical technique using photoactive fluorescence substances or sensitizers to indicate neoplastic tissue after illumination with (pseudo-) monochromatic light of the appropriate wavelength Citation[9]. Early studies using photosensitizing agents such as 5-aminolevulinic acid (5-ALA) have been shown to increase bladder tumor detection rates by 20–90% Citation[10]. Numerous clinical studies confirmed that PDD enabled the detection of more tumors, particularly CIS, compared with WLC. For example, a large series with 875 patients demonstrated increased sensitivity (5-ALA: 92% vs WLC: 76%) Citation[11]. Denzinger et al. reported a significant advantage of decreased BC recurrence after PDD, with recurrence-free survival of 71% in the PDD group versus 45% in the WLC group, persisting for at least 8 years Citation[12].
Inflammation, intravesical therapy, tangential illumination and hyperplasia have been reported to cause false-positive fluorescence resulting in a relative reduced specificity, ranging from 41 to 82% Citation[13]. A new derivative, hexaminolevulinate (HAL), which is a hexylesther of ALA, offers enhanced fluorescence in a shorter time and at lower concentrations. HAL or HEXVIX® (PhotoCure, Oslo, Norway) has been approved by the EU and is currently under review for regulatory approval in the USA Citation[1]. HAL offers an excellent safety profile and is easy to use Citation[14]. A Phase II trial showed improved overall sensitivity (HAL: 96% vs WLC: 73%) for HEXVIX cystoscopy Citation[15]. Jocham et al. demonstrated comparable results with greater overall sensitivity for HAL–PDD (97 vs 78% [WLC]) in 146 bladder cancer patients Citation[16]. Most recently, for the first time, a large prospective randomized Phase III multicenter trial with 766 randomized pTa/T1 patients demonstrated an overall reduction in the recurrence rate by 21% (HAL: 36% vs WLC: 46%) over a 9-month follow-up, and an improvement in CIS detection of 46% Citation[14].
Conclusion
The large human and economic burden of diagnosing and treating BC underscores the importance of optimizing diagnosis and treatment. Although cystoscopy and cytology remain the current standard in BC detection, small papillary and solid tumors, as well as CIS of the bladder, may easily be missed. Since patients with associated CIS have a significantly greater risk of progression, the accuracy and completeness of initial treatment takes on an added importance in these patients. Controlled studies have proven that PDD can enhance BC detection and treatment by better visualization of suspicious areas in the bladder. In addition to better detection of malignant and precancerous tissue, PDD enables a more complete resection of bladder tumors, resulting in less residual tumor tissue after primary TURBT. Various well-known factors, such as tumor size, number of tumors, presence of CIS, prior recurrence rate and the quality of TURBT, largely influence the early recurrence rate. Delayed diagnosis or insufficient resection with inaccurate tumor grading or staging result in an increased risk of cancer progression and subsequent complex and expensive treatments.
The primary goal of diagnosis and treatment of BC is complete eradiation of all visible tumor and, thus, cure. Initial higher costs for PDD, however, eventually lead to a reduction of overall treatment costs for BC after 3–7 years due to fewer follow-up TURBT Citation[17]. A recent German trial compared the costs during a 7-year follow-up of 301 patients and also revealed that PDD significantly reduced costs related to recurring BC Citation[18]. In summary, superior BC detection with PDD not only enhances visibility and improves TURBT, but provides maximal clinical benefit for patients by reducing recurrence rates, offers early-stage detection that leads to earlier treatment and more accurate clinical decisions, and lowers BC costs in the middle- and long-term.
Financial & competing interests disclosure
Arnulf Stenzl is a Speaker and Consultant for General Electric Company and a Researcher for Photocure ASA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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