Correspondence *Department of Urology, University Medical Centre, St Radboud, Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands

Email f.witjes@uro.umcn.nl

Introduction

Bladder cancer is the fourth most common malignancy among men in the Western world.¹ Urothelial cell carcinoma comprises 90% to 95% of all bladder cancers,² with about 70% presenting initially as non-muscle-invasive bladder cancer and the remainder as invasive cancer. Transurethral resection (TUR) of the bladder tumor is usually followed by adjuvant intravesical instillations to reduce the risk of recurrence and to prevent progression to muscle-invasive disease.

Recurrence and progression rates vary greatly depending on factors such as tumor multiplicity, size, previous recurrence rates, and tumor (T) stage, presence of carcinoma in situ (CIS) and grade.³ Recurrence rates range from 15% to 61% at 1 year and 31% to 78% at 5 years. At 5 years after treatment, tumor progression rates range from <1% to 45%. Oosterlinck et al.² used prognostic factors similar to those proposed by the EORTC (European Organisation for Research and Treatment of Cancer) group to classify non-muscle-invasive bladder cancer into low, intermediate and high-risk groups to enable the appropriate choice of adjuvant therapy.

Owing to high recurrence rates, the prevalence of non-muscle-invasive bladder cancer is high, making it a labor-intensive and costly disease to manage. Botteman et al.⁴ calculated that bladder cancer was the fifth most expensive cancer in overall cost, but was the most expensive per patient. They estimated the lifetime cost at US$96,000 to $187,000 per patient (2001 values), because of long-term survival and life-long monitoring and treatment. They concluded that current diagnostic processes, follow-up schedules and treatment are not cost-effective, particularly for non-muscle-invasive bladder cancer. Since then there have been no major developments in the management of bladder cancer, and there remains a low awareness of the issue of the cost-effectiveness of current patient management.

Avritscher et al.⁵ confirmed Botteman's findings with a study of bladder cancer costs based on a single-institution cohort. They found that approximately 60% of costs were related to treatment and 30% to complications. Lifetime costs were calculated using two extreme scenarios: in the first, recurrence occurred at a mean rate and definitive treatment was successful; in the other (worst case) scenario all patients died after progression to muscle-invasive disease. The lifetime costs were US$120,684 and $99,270, respectively.

These findings illustrate the need to improve care in bladder cancer, for medical reasons and also to use healthcare resources more effectively.

Detection and treatment of bladder tumors

When bladder cancer is initially suspected, the first diagnostic tool is visual inspection of the bladder with an endoscope and white-light illumination (white-light cystoscopy) for confirming the presence, location and type of tumor. Although white-light cystoscopy is reliable for exophytic tumors, flat carcinomas (particularly CIS), dysplasia, multifocal growth and microscopic lesions are much more difficult to detect. Urinary cytology, the second diagnostic tool in bladder cancer, is highly sensitive for detecting CIS, but epithelial changes might also be induced by chemotherapeutic agents, radiation, infection, repeated catheterization, electrocauterization and bladder washing,⁶ or renal or systemic disease.⁷ Interpretation of results is, therefore, highly dependent on the skill and experience of the cytopathologist. Karakiewicz et al.⁸ found that the ability of urinary cytology to predict recurrence of transitional cell carcinoma (TCC) varied greatly across 10 Canadian institutions, ranging from 63% to 89%.

Given the limitations of these two diagnostic tools, bladder tumors can be overlooked and inadequately resected during TUR. Published recurrence rates can, therefore, be misleading, as a significant proportion of so-called 'recurrences' are not new occurrences at all, but arise from residual tumor left behind at resection, or growth of previously undetected microscopic lesions.^{9, 10} Many studies have reported that residual tumor is 'routinely' detected at a second TUR.¹¹ Babjuk et al.⁹ reported the presence of malignant tissue in 32% to 36% of patients at second resection carried out 1–7 weeks after initial TUR, particularly in TaG3 disease and in multiple tumors. In a similar review, Daniltchenko¹² reported that early recurrences were detected in 30% to 40% of patients at a second TUR carried out within 6–8 weeks of the original surgery. When the site of the original tumor was resected for a second time, residual TCC was found in 44% of patients.¹³ For high-grade tumors, the rate can be as high as 70%.^{14, 15}

Photodynamic diagnosis

Photodynamic diagnosis (PDD) exploits the photoactive nature of certain compounds in order to enhance the visual demarcation between normal and neoplastic tissue. These agents accumulate preferentially in neoplastic tissue, and fluoresce in the visible spectrum when illuminated with light of the appropriate wavelength, enabling better visualization of suspicious tissue without the need for elaborate image-processing equipment.

Current photosensitizers, such as 5-aminolevulinic acid (ALA), accumulate preferentially in tumor tissue to a ratio of around 20:1 compared with normal tissue.¹⁶ The mechanisms are still not fully understood, but studies suggest that accumulation is not due to selective uptake by cancerous cells. Rather, there are similar levels of uptake in all cell types, but the processes of conversion and elimination are different in malignant cells, leading to a concentration gradient between neoplastic and normal tissue.¹⁶

In theory, many photosensitizers can be used in bladder cancer. In practice, agents such as ALA and its derivatives are preferred, as they can be administered topically via instillation into the bladder. This avoids the lengthy residual skin photosensitization that occurs with systemically administered photosensitizers such as hematoporphyrin derivative (HpD).

In the biosynthesis of heme, endogenous ALA is a natural precursor of the photoactive intermediate protoporphyrin IX (PpIX). The subsequent conversion of PpIX into heme is relatively slow, and the application of exogenous ALA can, therefore, lead to accumulation of clinically significant concentrations of PpIX.¹⁷ When illuminated with violet light between 375 nm and 440 nm, PpIX returns to a lower energy level partly by emitting red fluorescence, which can be detected and used for diagnostic purposes. The fluorescence from malignant tissue appears bright and sharply demarcated, whereas fluorescence from nonmalignant tissue, such as along blood vessels and in areas of mucosal inflammation, appears pinkish, without clear demarcation.

Fluorescence cystoscopy with 5-aminolevulinic acid

Early studies using ALA in bladder tumors confirmed that there was good demarcation between red fluorescence from malignant tissue and background-reflected blue light. In an early clinical study to assess the predictive potential of PDD with ALA, the correlation between fluorescence and histology findings in 68 patients gave a sensitivity of 100% and a specificity of 68.5%.¹⁸ In this study, 26 malignant or precancerous lesions missed during routine cystoscopy were found during PDD—a finding supported by many subsequent studies with ALA^{19, 20, 21} and other agents^{22, 23, 24} (Table 1).

Table 1 Reported sensitivity and specificity (by lesion) of fluorescent cystoscopy and white light cystoscopy.

Full tableFigures & Tables indexDownload Power Point slide (244K)

Although ALA is useful, its bioavailability is low and its distribution in malignant tissue is heterogeneous. Relatively high concentrations of ALA must be instilled for several hours to be effective, but even after this time fluorescence microscopy still shows an irregular distribution of PpIX within superficial tumors.²⁵ As ALA is a double-charged molecule that does not easily penetrate cell membranes and interstitial spaces, it was anticipated that lipophilic derivatives of ALA would be more effective. Marti et al.²⁶ subsequently demonstrated that the hexyl ester of ALA (hexaminolevulinic acid, HAL) produced at least twice the fluorescence of ALA but at a concentration 45 times lower. Furthermore, the fluorescence effect was produced more quickly, in 2 hours. The authors also demonstrated that, while ALA fluorescence is limited, mainly to the superficial cells in the urothelium, HAL fluorescence is distributed throughout all urothelial layers.

Specificity of fluorescence cystoscopy

When using a diagnostic tool, it is common see to more false-positives as the number of true-positives increases (Table 1).

False-positives encountered during fluorescence cystoscopy are attributable to a number of factors. The higher cellular turnover in areas of scarring or residual inflammation leads to a preferential accumulation of ALA similar to that in malignant tissue, and hence to areas of fluorescence.³¹ Biopsies of fluorescing but nonmalignant tissue have indicated that florid cystitis, hyperplastic urothelium or hyperemic submucosa are significantly more frequently false-positive than chronically inflamed or edematous urothelium.¹⁹ These are also the areas that pose the greatest difficulty for diagnosis using white-light cystoscopy.

Kriegmair et al.¹⁹ noted particularly poor specificity of fluorescence cystoscopy in the trigone, bladder neck and anterior bladder wall, possibly due to a higher proportion of inflammatory changes, although this was not confirmed. Jichlinski³¹ speculated that false positives can arise from oblique illumination of the mucosa if the distal end of the endoscope is too close to the bladder wall. This effect is also observed during white-light cystoscopy because of the differential propagation of green and red light in tissues. Filbeck³² reported that the sensitivity of ALA fluorescence cystoscopy is reduced in a second TUR due to an increased number of false-negatives and false-positives, but also noted that in all parameters measured, fluorescence diagnosis was still superior to white-light cystoscopy.

The accuracy of fluorescence cystoscopy is also affected by previous bladder treatments. As Grimbergen demonstrated,³³ intravesical therapy within the 6-month period before fluorescence endoscopy with ALA results in significantly more false-positive fluorescence biopsies. However, the authors of this study conclude that the technique is justified, given the importance of early detection and treatment of malignant or premalignant tissue.

Significantly, 58% of false-positive PpIX-fluorescing specimens displayed genetic changes similar to those in papillary carcinomas found in the same patients, indicating the possibility for future malignant proliferation.³⁴ This finding indicates that there could actually be fewer real 'false-positives' than are defined by standard pathological classifications.

Does fluorescence cystoscopy impact on patient management?

In an early study on fluorescence cystoscopy,¹⁹ 35 lesions were detected solely by fluorescence cystoscopy: two were CIS and one was a muscle-invasive tumor; the other 32 were dysplasias (12) or superficial tumors (20). An accompanying editorial comment said: "I am not impressed by the ability to detect important tumors of the bladder ... [using 5-ALA fluorescence] .. and ...Dysplasia is not cancer and does not require therapy. Assuming progressive growth, [the 20 superficial tumors] would have been observed and removed within 3 to 6 months."³⁵ It is reasonable to question the clinical relevance of detecting more tumors, although most clinicians would probably ask why urologists should refrain from resecting tumors even if they are low risk. The possible clinical benefit of improved tumor detection has been assessed by Filbeck et al.³⁶ and Jocham et al.,²⁴ who studied the impact of improved tumor detection on patient management. Filbeck et al.³⁶ treated 177 patients that either had a tumor or moderate dysplasia (DII). Resection under white light was followed by resection under blue light of all remaining fluorescing areas using ALA. Fifty of 336 tumors were overlooked using white light, particularly CIS (17/30 missed) and DII (7/16 missed).

In terms of patient management, tumor or DII was detected in nine patients only through fluorescence cystoscopy (three had tumors of stage TaG1–G2, two had CIS, one had a >T1 lesion, and three had DII). Where fluorescence cystoscopy detected additional tumors, eight patients were restaged, and a further 10 were reclassified from solitary to multiple tumors. Interestingly, given the 1996 editorial comment on dysplasia, at next follow up, two of the three patients with DII were found to have developed a TaG1–G2 tumor and CIS. This supports the findings of an earlier study,³⁷ which reported that the presence of dysplasia or CIS increased the risk of progression by approximately 80%. Thus, in this study there was a change in treatment strategy for 27 patients (9%).³⁷

A different study design was adopted by Jocham et al.²⁴ An independent urologist, blinded to the diagnostic technique, recommended management plans for 146 patients after reviewing anonymous medical history, pathology and cystoscopy results. Two sets of records were assembled for each patient: one with white-light cystoscopy results and the other with fluorescence cystoscopy. Records were presented in random batches and the two recommended management plans for each patient were subsequently compared. HAL fluorescence cystoscopy detected a greater number of tumors and dysplasia than white light, and led to the recommendation of additional postoperative procedures in a total of 15 patients, while in a further 10, more extensive resection was indicated. As a percentage of patients with verified tumors, fluorescence cystoscopy led to improved treatment in 21.7% of patients.

Early detection, therefore, frequently leads to a change in treatment plan. The detection of tumors with an unfavorable prognosis might indicate that early cystectomy should be used instead of individual tumor resection, and patients with previously undetected CIS can receive early treatment with bacillus Calmette–Guerin (BCG). Patients with DII are more likely to be followed closely: the risk of DII patients developing an invasive tumor is around 15%, and genetic data suggest that DII is a precursor of CIS.³⁸ More 'appropriate' treatment might also be less aggressive. Jocham describes two cases where CIS, concomitant with other cancer, was only detected with fluorescence cystoscopy.²⁴ Without this information, the CIS may have been detected at follow-up and interpreted as treatment failure, leading to cystectomy. Early detection enabled treatment with additional BCG, thus avoiding irreversible surgery.

The detection of further papillary tumors does not indicate major changes in treatment, but enables a more precise and complete resection to be carried out and spares the patient extra procedures. Moreover, at cystoscopy carried out 3 months after initial treatment, when residual tumor might still present after inadequate resection plus instillation therapy, residual disease could be mistakenly interpreted as treatment failure. Fluorescence-guided TUR can reduce the rate of residual tumor by 50–80%, and avoid unnecessarily aggressive therapy.^{36, 39, 40}

Impact of fluorescence cystoscopy on recurrence rates

Data from patients treated in the late 1990s is now emerging, making it possible to assess the effect of improved detection and subsequent changes in patient management on recurrence rates (Table 2).

Table 2 Reported recurrence-free survival following white-light and fluorescence cystoscopy.

Full tableFigures & Tables indexDownload Power Point slide (222K)

In a recently published follow up to the 4-year data from their prospective randomized study,⁴¹ Denzinger et al.⁴² report recurrence-free survival (RFS) at 2, 4, 6 and 8 years after TUR, of 88%, 84%, 79% and 71%, respectively, in the ALA fluorescence group, and 73%, 64%, 54% and 45%, respectively, in the white-light group. The residual tumor rate was 4.5% in the ALA group against 25.2% in the white-light group (P <0.0001). The differences were statistically significant and independent of risk group.

Babjuk and colleagues⁹ found significantly better RFS rates at 1 and 2 years in 122 Ta/T1 patients treated with fluorescence-guided TUR: 66% and 40%, respectively, compared to 39% and 28%, respectively, with white light. At the time of first follow-up cystoscopy, 10–15 weeks after TUR, tumor recurrence was detected in 37% of patients investigated with white-light cystoscopy compared with 8% in the fluorescence cystoscopy group. The most significant benefit of this diagnostic technique was seen in patients with multiple and recurrent tumors.

A similar study by Daniltchenko and colleagues¹² reported 5-year follow-up results of 115 patients randomized to receive TUR guided either by white-light or ALA fluorescence cystoscopy. Median time to first recurrence was 5 months in the standard and 12 months in the fluorescence group, with 5-year RFS of 25% and 41%, respectively. The lower RFS rates compared to those reported by Filbeck⁴¹ are attributed to greater use of adjuvant intravesical therapy in the Filbeck study than in that by Daniltchenko et al. Tumor progression to muscle invasion or metastasis was also significantly reduced in the ALA group compared with the white-light group (18% vs 8%, respectively). After the first TUR, all subsequent inspections and TURs were carried out with ALA cystoscopy, suggesting that the differences might have been greater if the two groups had continued to be treated differently. Daniltchenko also noted a clear economic advantage with fluorescence cystoscopy, with the cost of 21 additional TURs required with white light in this patient group overall being saved over 5 years.¹² Studies are currently under way to assess whether HAL-guided diagnosis and treatment has a similar effect to ALA cystoscopy on recurrence rates.

Financial implications of fluorescence cystoscopy

The impact of reduced recurrence rates on healthcare costs should not be underestimated. The additional cost of the light source and optics for fluorescence cystoscopy is 15,000–17,000 and a specifically designed video camera is between 8,000 and 10,000. However, these costs can be amortized over other applications. In 2001, Stenzl et al. reported considerable savings over 3 years owing to a 6% decrease in residual tumors.⁴³ More recently, Burger et al.⁴⁴ reported a cost analysis based on 7-year follow-up of 301 patients with non-muscle-invasive bladder cancer who were randomized to white-light or fluorescence cystoscopy. Recurrence was higher in the white-light group, 42% vs 18%, leading to more TURs (2.0 per patient compared to 0.8 per patient after fluorescence cystoscopy). In the white-light group there was an average of one recurrence per patient compared with 0.3 in the fluorescence cystoscopy group, resulting in costs of 1,750 per white-light patient compared to 420 after fluorescence cystoscopy. A single cost of 135 per patient was allocated for fluorescence cystoscopy, but the overall cost saved for each fluorescence cystoscopy patient per year was 168.

Future of fluorescence cystoscopy in bladder cancer

ALA-guided fluorescence cystoscopy is already widely used, and in March 2005 HAL was approved in Europe for the diagnosis of bladder cancer. The approval process continues in the US.

Technical improvements to enhance the visual demarcation between malignant and nonmalignant tissue are anticipated. Zaak⁴⁵ and others have already reported on image quantification, which is expected to reduce the false-positive rate by 30%.

Outpatient cystoscopic follow-up is usually carried out with flexible cystoscopes, and two small-scale studies using HAL fluorescence have shown that fluorescence-guided flexible cystoscopy produces results comparable with HAL rigid cystoscopy, and that both are more accurate than standard white-light cystoscopy.^{46, 47} This development would markedly increase the utility of fluorescence-enhanced cystoscopy.

Many other photosensitizers are under investigation, but the most promising appears to be hypericin, a naturally occurring quinone found in Hypericum perforatum (St John's wort). D'Hallewin⁴⁸ reports 94% sensitivity and 95% specificity using hypericin as a photosensitizing agent for detecting bladder tumors.

The phenomenon of fluorescence could also improve the performance of urinary cytology. ALA^{49, 50} and hypericin^{50, 51} have both been assessed as possible ex vivo cell markers. Both studies report that suspicious cells showed good fluorescence under the microscope, leading to an improvement in sensitivity. A preliminary report on flow cytometry, after incubation of urine samples with HAL, suggested that the technique might be feasible for the detection of bladder cancer cells in urine.⁵²

Conclusions

The high lifetime cost of diagnosing, monitoring and treating bladder cancer emphasizes the need for improvements in the detection and management of bladder cancer patients. Fluorescence cystoscopy using HAL to assist visualization improves the detection rate of bladder tumors, particularly CIS, compared to white-light cystoscopy. This leads to improved treatment in a significant number of patients. Studies are ongoing to assess whether this results in reduced recurrence rates, as has already been shown with ALA, or improved cure rates through more appropriate treatment.

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Subject areas under which this article appears: Urologic oncology (nonprostatic)