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Therapeutic Value for Carcinoma In Situ of the Bladder? No (a difficult task)
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OPPOSING VIEWS
both compounds is considered similar.2 Moreover, HAL is the only registered compound for FC. Similarly, most studies have included patients with papillary tumors and CIS. However, since the improved detection rate is especially notable for CIS and the consequences of missing CIS are much more serious than missing a low grade papillary tumor, a positive cost-effective calculation is even more relevant in CIS cases.2
The conclusion is simple. HAL-FC improves identification of papillary bladder tumors and especially CIS, resulting in better therapy, longer recurrence-free intervals, improved patient care and reduced costs. J. A. Witjes Department of Urology Radboud University Nijmegen Medical Centre Nijmegen, the Netherlands
REFERENCES 1. Botteman MF, Pashos CL, Redaelli A et al: The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics 2003; 21: 1315.
2. Kausch I, Sommerauer M, Montorsi F et al: Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumu-
lative analysis of prospective studies. Eur Urol 2010; 57: 595. 3. Feifer A, Xie X, Brophy JM et al: Contemporary cost analysis of single instillation of mitomycin after transurethral resection of bladder tumor in a universal health care system. Urology 2010; 76: 652. 4. Burger M, Zaak D, Stief CG et al: Photodynamic diagnostics and noninvasive bladder cancer: is
NO (a difficult task) How can I possibly make the case against a technique that provides such stunning images of such a dangerous tumor (see figure), that has given us new insights into the anatomy of CIS and that is so manifestly a brilliant diagnostic tool? The images are certainly beautiful but in the end it is not about the images, but about the results. How often does fluorescence cystoscopy identify CIS that changes a therapeutic decision? Not just an extra patch of CIS in addition to the patches that conventional white light cystoscopy had already identified, but the only CIS in a bladder. The answer is rarely, and disappointingly this issue is not often discussed in reports on the value of photodynamic diagnosis. Moreover, even if the patch identified is only seen under blue light, how often is that patch not associated with a high grade papillary or solid
it cost-effective in long-term application? A Germany-based cost analysis. Eur Urol 2007; 52: 142. 5. Stenzl A, Jocham D, Jichlinski P et al: Photodynamic diagnostics in the urinary tract. Consensus paper of the Working Group for Oncology of the German Society for Urology. Urologe A 2008; 47: 982.
tumor whose presence alone is enough to mandate a decision for BCG? I would propose that the latter scenario is rare indeed. There is no evidence that BCG is more effective for bladder tumors diagnosed and resected under blue light, as BCG treats CIS wherever it is in the bladder. What about other situations in which CIS is diagnosed? For suspected primary CIS, patients have urinary frequency and urgency. Voided urine cytology will be positive and biopsies under white light of the inevitable red patches will confirm the diagnosis. CIS is often found in conjunction with invasive tumors usually adjacent to the main tumor and will be detected at transurethral resection or in biopsies of red patches. If the decision for cystectomy is based on the presence of a muscle invasive tumor, then detection of distant satellites of CIS is irrelevant. Fluorescence cystoscopy in cases of CIS after BCG is fraught with difficulty because of false fluorescence
OPPOSING VIEWS
from inflamed bladder mucosa secondary to the BCG.1 The situation is further complicated in the U.S. because hexaminolevulinate is approved for just a single use. How can one base treatment of a patient receiving BCG on a technique that can only be applied for a single cystoscopy? There are scenarios when fluorescence cystoscopy can be helpful in the context of CIS. In the rare situation of assessment of “positive urinary cytology/ negative white light cystoscopy” fluorescence cystoscopy did identify bladder cancer in 20% of patients, thus sparing them unnecessary ureterorenoscopy.2 In patients with tumor in a bladder diverticulum fluorescence cystoscopy can be useful to exclude disease in the rest of the bladder if a conservative excision, ie diverticulectomy, is favored. I would suggest that the primary goal to improve outcomes for NMIBC is not better diagnostics but better therapy. Would it be better to add fluorescence cystoscopy to every urology department in the U.S. or Electromotive Drug Administration (EMDA) technology to deliver EMDA mitomycin C? The hardware is less expensive (⬃£8k vs ⬃ £50k in the UK). When EMDA mitomycin C was combined in sequential fashion with BCG in a multicenter randomized trial outcomes for pT1 bladder cancers improved.3 Our experience with sequential BCG/ EMDA mitomycin has been positive.4 Need it be an “either” “or” situation? In an ideal world, such as that before the 2008 financial crash, one
21
might put the best diagnostic technology (ie fluorescence cystoscopy) and the best therapeutic technologies (possibly EMDA) into every urology department. However, Europe and the U.S. are mired in debt and urologists are not exempt from the responsibility to spend money wisely. The studies on cost-effectiveness of fluorescence cystoscopy are distorted because they comprise studies of the largest and as yet unrepeated clinical effects. Fluorescence cystoscopy can become expensive, and it was the largest drug expenditure in urology at £44k in 2010 at Guys Hospital in London. At the Food and Drug Administration in 2009 when hexaminolevulinate came up for review an oncologist on the advisory board made an interesting comment that has stuck with me: “is it fair to blame a brilliant diagnostic technique for the limitations of bladder cancer treatment as currently practised?” Of course it is not. After all one doesn’t expect computerized tomography to improve outcomes but merely diagnostics. However, simply hoping that fluorescence cystoscopy will markedly improve outcomes in this disease may be futile. Yet another “improved means to an unimproved end.”5 Timothy O’Brien Urology Centre Guys and St. Thomas Hospitals London, UK
REFERENCES 1. Ray ER, Chatterton K, Khan MS et al: Hexaminolevulinate fluorescence cystoscopy in patients previously treated with intravesical Bacille-CalmetteGuérin. BJU Int 2010; 105: 789. 2. Ray ER, Chatterton K, Khan S et al: Hexaminolevulinate “blue light” fluorescence cystoscopy in the investigation of clinically unconfirmed
positive urine cytology. BJU Int 2009; 103: 1363. 3. Di Stasi SM, Giannantoni A, Giurioli A et al: Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol 2006; 7: 43.
4. Amery S, Chatterton K, Zisengwe G et al: Initial experience with sequential BCG/electromotive drug administration (EMDA) mitomycin C as the standard intravesical regimen for high risk nonmuscle invasive bladder cancer. BJU Int 2012; 109: 35. 5. Quote from Henry David Thoreau. American essayist poet and philosopher (1817–1862).
OPPOSING VIEWS
both compounds is considered similar.2 Moreover, HAL is the only registered compound for FC. Similarly, most studies have included patients with papillary tumors and CIS. However, since the improved detection rate is especially notable for CIS and the consequences of missing CIS are much more serious than missing a low grade papillary tumor, a positive cost-effective calculation is even more relevant in CIS cases.2
The conclusion is simple. HAL-FC improves identification of papillary bladder tumors and especially CIS, resulting in better therapy, longer recurrence-free intervals, improved patient care and reduced costs. J. A. Witjes Department of Urology Radboud University Nijmegen Medical Centre Nijmegen, the Netherlands
REFERENCES 1. Botteman MF, Pashos CL, Redaelli A et al: The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics 2003; 21: 1315.
2. Kausch I, Sommerauer M, Montorsi F et al: Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumu-
lative analysis of prospective studies. Eur Urol 2010; 57: 595. 3. Feifer A, Xie X, Brophy JM et al: Contemporary cost analysis of single instillation of mitomycin after transurethral resection of bladder tumor in a universal health care system. Urology 2010; 76: 652. 4. Burger M, Zaak D, Stief CG et al: Photodynamic diagnostics and noninvasive bladder cancer: is
NO (a difficult task) How can I possibly make the case against a technique that provides such stunning images of such a dangerous tumor (see figure), that has given us new insights into the anatomy of CIS and that is so manifestly a brilliant diagnostic tool? The images are certainly beautiful but in the end it is not about the images, but about the results. How often does fluorescence cystoscopy identify CIS that changes a therapeutic decision? Not just an extra patch of CIS in addition to the patches that conventional white light cystoscopy had already identified, but the only CIS in a bladder. The answer is rarely, and disappointingly this issue is not often discussed in reports on the value of photodynamic diagnosis. Moreover, even if the patch identified is only seen under blue light, how often is that patch not associated with a high grade papillary or solid
it cost-effective in long-term application? A Germany-based cost analysis. Eur Urol 2007; 52: 142. 5. Stenzl A, Jocham D, Jichlinski P et al: Photodynamic diagnostics in the urinary tract. Consensus paper of the Working Group for Oncology of the German Society for Urology. Urologe A 2008; 47: 982.
tumor whose presence alone is enough to mandate a decision for BCG? I would propose that the latter scenario is rare indeed. There is no evidence that BCG is more effective for bladder tumors diagnosed and resected under blue light, as BCG treats CIS wherever it is in the bladder. What about other situations in which CIS is diagnosed? For suspected primary CIS, patients have urinary frequency and urgency. Voided urine cytology will be positive and biopsies under white light of the inevitable red patches will confirm the diagnosis. CIS is often found in conjunction with invasive tumors usually adjacent to the main tumor and will be detected at transurethral resection or in biopsies of red patches. If the decision for cystectomy is based on the presence of a muscle invasive tumor, then detection of distant satellites of CIS is irrelevant. Fluorescence cystoscopy in cases of CIS after BCG is fraught with difficulty because of false fluorescence
OPPOSING VIEWS
from inflamed bladder mucosa secondary to the BCG.1 The situation is further complicated in the U.S. because hexaminolevulinate is approved for just a single use. How can one base treatment of a patient receiving BCG on a technique that can only be applied for a single cystoscopy? There are scenarios when fluorescence cystoscopy can be helpful in the context of CIS. In the rare situation of assessment of “positive urinary cytology/ negative white light cystoscopy” fluorescence cystoscopy did identify bladder cancer in 20% of patients, thus sparing them unnecessary ureterorenoscopy.2 In patients with tumor in a bladder diverticulum fluorescence cystoscopy can be useful to exclude disease in the rest of the bladder if a conservative excision, ie diverticulectomy, is favored. I would suggest that the primary goal to improve outcomes for NMIBC is not better diagnostics but better therapy. Would it be better to add fluorescence cystoscopy to every urology department in the U.S. or Electromotive Drug Administration (EMDA) technology to deliver EMDA mitomycin C? The hardware is less expensive (⬃£8k vs ⬃ £50k in the UK). When EMDA mitomycin C was combined in sequential fashion with BCG in a multicenter randomized trial outcomes for pT1 bladder cancers improved.3 Our experience with sequential BCG/ EMDA mitomycin has been positive.4 Need it be an “either” “or” situation? In an ideal world, such as that before the 2008 financial crash, one
21
might put the best diagnostic technology (ie fluorescence cystoscopy) and the best therapeutic technologies (possibly EMDA) into every urology department. However, Europe and the U.S. are mired in debt and urologists are not exempt from the responsibility to spend money wisely. The studies on cost-effectiveness of fluorescence cystoscopy are distorted because they comprise studies of the largest and as yet unrepeated clinical effects. Fluorescence cystoscopy can become expensive, and it was the largest drug expenditure in urology at £44k in 2010 at Guys Hospital in London. At the Food and Drug Administration in 2009 when hexaminolevulinate came up for review an oncologist on the advisory board made an interesting comment that has stuck with me: “is it fair to blame a brilliant diagnostic technique for the limitations of bladder cancer treatment as currently practised?” Of course it is not. After all one doesn’t expect computerized tomography to improve outcomes but merely diagnostics. However, simply hoping that fluorescence cystoscopy will markedly improve outcomes in this disease may be futile. Yet another “improved means to an unimproved end.”5 Timothy O’Brien Urology Centre Guys and St. Thomas Hospitals London, UK
REFERENCES 1. Ray ER, Chatterton K, Khan MS et al: Hexaminolevulinate fluorescence cystoscopy in patients previously treated with intravesical Bacille-CalmetteGuérin. BJU Int 2010; 105: 789. 2. Ray ER, Chatterton K, Khan S et al: Hexaminolevulinate “blue light” fluorescence cystoscopy in the investigation of clinically unconfirmed
positive urine cytology. BJU Int 2009; 103: 1363. 3. Di Stasi SM, Giannantoni A, Giurioli A et al: Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol 2006; 7: 43.
4. Amery S, Chatterton K, Zisengwe G et al: Initial experience with sequential BCG/electromotive drug administration (EMDA) mitomycin C as the standard intravesical regimen for high risk nonmuscle invasive bladder cancer. BJU Int 2012; 109: 35. 5. Quote from Henry David Thoreau. American essayist poet and philosopher (1817–1862).