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Cost-Effectiveness of Fluorescent Cystoscopy for Noninvasive Papillary Tumors
Opposing Views
Cost-Effectiveness of Fluorescent Cystoscopy for Noninvasive Papillary Tumors THE initial resection of bladder tumors is inadequate in many patients, and the recurrence rates at first followup are as high as 20% for solitary tumors and 45% for multiple tumors.1 Use of white light (WL) cystoscopy has been shown to miss some bladder cancers, especially areas of dysplasia and carcinoma in situ. As such, fluorescence based photodynamic diagnostic (PDD) techniques have been developed to take advantage of the fact that photoactive compounds accumulate in neoplastic tissue compared to normal tissue and fluoresce red under blue light illumination.2 Initially ␦-aminolevulinic acid (5-ALA) was used for PDD but it was limited by low bioavailability and heterogeneous distribution in neoplastic tissues.3 Subsequently more potent lipophilic derivates such as hexyl aminolevulinate (HAL) were developed which increased the amount of photoactive porphyrins produced within a shorter period at lower drug doses, allowing significantly shorter bladder instillation time and better cystoscopic examination.4 Two phase III multicenter studies of patients with noninvasive bladder cancer revealed increased detection rates for dysplasia, Ta and T1 tumors.5,6 Although these results were considered sufficient for the approval and adoption of HAL fluorescent cystoscopy in Europe, the Food and Drug Administration required for its approval a strict prospective trial that demonstrated a reduction in bladder recurrence when fluorescent transurethral resection of bladder tumors (TURBT) was performed compared to WL TURBT.7 Should PDD be used for every TURBT? What is the cost-effectiveness of using fluorescent TURBT given the costs of acquiring the instruments needed and the ongoing cost of HAL as well as indirect costs associated with instillation? We debate the cost-effectiveness of PDD for the management of noninvasive bladder cancer.
PRO Bladder cancer with its lifelong monitoring and multiple recurrences is one of the most costly malignancies to manage from diagnosis to death. Two-thirds 0022-5347/12/1875-1537/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
of the overall costs are related to TURBT for nonmuscle invasive bladder cancer. Thus, reducing the number of TURBTs required is likely to have the most significant impact on cost reduction. The initial observations that fluorescent cystoscopy can be effective in detecting flat lesions missed by standard WL cystoscopy have been confirmed by many studies, including the Food and Drug Administration registration randomized TURBT trial which showed that of 41 patients with carcinoma in situ found by HAL cystoscopy 13 (32%) did not have carcinoma in situ detected by WL (p ⬍0.0001).8 Perhaps more surprising and directly related to the topic of this debate is the finding in most studies that even expert surgeons using optimal WL modern instruments will miss 1 or more papillary tumors in approximately 20% of cases. In the Food and Drug Administration trial of WL vs HAL TURBT, which included several investigators newly trained in the technique, at least 1 tumor was seen only with fluorescence in 16% of patients (p⫽0.001).7 Resection of these additional tumors resulted in a 16% relative reduction in recurrence at 9 months. With longer followup (median 55 months) HAL TURBT had a longer time to first recurrence of 16.4 months vs 9.6 months for WL (p⫽0.04).8 Moreover, 20% more patients (31.8% vs 38%) had no recurrence in more than 4 years. European studies from early adopters provided evidence that, although PDD requires investment in equipment and is associated with ongoing costs for the purchase of the fluorescent agent, this higher overall cost is recouped via greater diagnostic accuracy, a lower rate of disease recurrence and reduced overall disease management expenditures.9 In a study of 191 patients with nonmuscle invasive bladder cancer randomized to initial WL vs PDD TURBT, a median followup of 85 months and observed recurrence rate of 46% the conclusion was that PDD related expenditures were reimbursed within the first year. However, the potential of additional benefit of repeated use of HAL TURBT in patients with recurrence cannot be assessed by existing literature based on a single initial use of the technique. Of 327 Vol. 187, 1537-1539, May 2012 Printed in U.S.A. DOI:10.1016/j.juro.2012.02.2563
www.jurology.com
1537
1538
OPPOSING VIEWS
patients with recurrent bladder cancer at baseline the absolute reduction of recurrence was 11.2% (50.6% for HAL vs 61.8% for WL).7 This observation suggests that past the cost neutral initial year, use of HAL TURBT for all subsequent recurrences will result in significant cumulative cost savings. An immediate intravesical, single dose instillation of mitomycin C (MMC) after TURBT is currently recommended in all guidelines because it delays recurrence in 15% to 20% of cases. Nevertheless, it is wellknown that a majority of urologists in the United States and Europe do not prescribe perioperative MMC for a number of reasons including operating room strict guidelines on administration of chemotherapy, lack of experience of nursing personnel in handling chemotherapy drugs, and concern about deep resection and delayed healing often noted several months after TURBT and MMC. Also, not all remaining papillary tumors will be sensitive to chemotherapy while TURBT will effectively eliminate those that have been visualized. HAL TURBT has little toxicity and can be used in all patients. It helps the surgeons perform a more complete resection, the procedure can be learned rapidly and the instrumentation can also be used for routine standard WL cystoscopies. Could the use of post-TURBT MMC outweigh the benefits of HAL TURBT? This question has been recently addressed in a single institution trial that randomized patients to WL vs HAL TURBT with all patients receiving perioperative MMC.10 A 28.5% risk reduction of tumor recurrence was noted in the HAL TURBT group with a 2-year rate of 32.5% vs 45.6% for WL. Clearly HAL TURBT for all nonmuscle invasive bladder cancer will result in better patient care and significant overall cost reduction for the lifelong management of this disease. Moreover, it will result in significant improvement in quality of life as well as other cost benefits to the patient, such as societal advantages of gained wages and productivity owing to decreases in disease recurrence and need for surgery. Yves Fradet Centre Hospitalier Universitaire de Quebec Quebec, Canada
CON The cost of a new technology is relatively objective. There are costs of necessary equipment, which in this case includes PDD scopes and D light units with cables and monitors. Such capital equipment is reusable for many cases and usually amortized over 7 years. Cost estimates obtained from Karl Storz Inc. for all capital equipment is approximately $90,000. The cost per case for the capital equipment will
depend on volume. A relatively high volume practice may perform 100 TURBTs a year resulting in a cost per case of approximately $128. There is also cost of Hexvix® used in each case with the price per Cysview® kit of $600. As such each case would have a direct cost of around $728. The majority of the cost of PDD is from instillation of Hexvix and cost of capital equipment is a relatively small percentage of overall cost. Based on this fact, even a much higher case volume will not dramatically reduce the cost of PDD. The direct cost calculated of $728 does not include the cost of nursing for instilling the Hexvix or the cost to the facility of housing a patient for the hour required to have the Hexvix instilled in the bladder. The cost of TURBT has been estimated around $3,800,11 which results in a cost ratio of about 5:1. In other words, 1 TURBT would have to be avoided for every 5 fluorescent cystoscopy procedures performed to achieve cost equivalence. Obviously this ratio can vary depending on the cost of TURBT at each institution which can vary, and potential indirect costs associated with loss of work and potential complications. The issue of efficiency is probably the more important question to address since one might consider the added expense to be acceptable if the benefits are great. One can agree that meaningful outcomes for bladder cancer include survival, progression and recurrence in that order. To my knowledge, no analyses thus far have demonstrated improved survival due to PDD. Several studies have evaluated the benefit of PDD in regard to progression but none has found a benefit.7,12–14 It should be noted that progression was not the primary end point of any study to date. Nevertheless, the main potential benefit identified is the risk of recurrence. Several single center studies have noted reduced recurrence rates using 5-ALA PDD compared to WL.14,15 However, 2 prospective randomized studies revealed no significant differences between the 5-ALA and WL groups with regard to recurrence-free and progression-free survival rates.12,13 Hexvix has the purported advantage over ALA of producing an increased amount of photoactive porphyrins within a shorter period at lower drug doses, allowing significantly shorter bladder instillation time and better cystoscopic examination.4 A prospective, randomized multicenter study enrolled 814 patients suspected of having bladder cancer at increased risk for recurrence based on more than 1 initial or recurrent bladder tumor within 12 months of a previous bladder tumor.7 During the 9-month followup (intent to treat) tumor recurred in 128 of 271 patients (47%) in the fluorescence group and 157 of 280 (56%) in the WL group (p⫽0.026) with a relative reduction in recurrence of 16%. The recur-
OPPOSING VIEWS
rence in low grade Ta was 45.4% vs 55.4% in the PDD and WL groups, respectively (p⫽0.02). However, in the patients with Ta high grade and T1 tumors the recurrence was 54.8% vs 56.6% in the PDD and WL groups, respectively (p⫽0.48). As such, the only demonstrated benefit is in reduction of recurrent low grade noninvasive tumors. This study was limited to higher risk patients, and so whether such a benefit will also be present in patients with typical risk of recurrence remains to be seen. The study was also optimized for performance of PDD by excluding patients with hematuria and those who received bacillus Calmette-Guérin or chemotherapy within 3 months. Furthermore, the first 5 patients enrolled in the study were excluded to reduce issues with learning curves. Taken together, the benefits of PDD with HAL appear minimal with a number needed to treat of more than 6 to
1539
prevent 1 TURBT in a patient with a low grade noninvasive tumor. This rate exceeds the threshold of cost-effectiveness based on the aforementioned discussion of cost. There are also practical needs that make PDD difficult, including patients must present an hour earlier for instillation, someone is required to instill the Hexvix and a surgeon must be present to evaluate the bladder using WL and PDD. In conclusion, for patients with noninvasive papillary tumors, the use of PDD has practical limitations, limited efficacy in reducing recurrence that is confined to low grade tumors and costs that exceed benefits. Yair Lotan Department of Urology University of Texas Southwestern Medical Center Dallas, Texas
REFERENCES 1. Brausi M, Collette L, Kurth K et al: Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol 2002; 41: 523. 2. Krieg RC, Messmann H, Rauch J et al: Metabolic characterization of tumor cell-specific protoporphyrin IX accumulation after exposure to 5-aminolevulinic acid in human colonic cells. Photochem Photobiol 2002; 76: 518. 3. Witjes JA and Douglass J: The role of hexaminolevulinate fluorescence cystoscopy in bladder cancer. Nat Clin Pract Urol 2007; 4: 542. 4. Jichlinski P, Guillou L, Karlsen SJ et al: Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer—a multicenter study. J Urol 2003; 170: 226. 5. Grossman HB, Gomella L, Fradet Y et al: A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol 2007; 178: 62.
6. Jocham D, Witjes F, Wagner S et al: Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol 2005; 174: 862. 7. Stenzl A, Burger M, Fradet Y et al: Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol 2010; 184: 1907. 8. Grossman HB, Natale RB, Tangen CM et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859. 9. Zaak D, Wieland WF, Stief CG et al: Routine use of photodynamic diagnosis of bladder cancer: practical and economic issues. Eur Urol, suppl., 2008; 7: 536. 10. Geavlete B, Multescu R, Georgescu D et al: Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? BJU Int 2012; 109: 549. 11. Lotan Y, Svatek RS and Sagalowsky AI: Should we screen for bladder cancer in a high-risk pop-
ulation? A cost per life-year saved analysis. Cancer 2006; 107: 982. 12. Schumacher MC, Holmang S, Davidsson T et al: Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic acid under visible and fluorescent light: results of a prospective, randomised, multicentre study. Eur Urol 2010; 57: 293. 13. Stenzl A, Penkoff H, Dajc-Sommerer E et al: Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy: a multicenter randomized, double-blind, placebo-controlled trial. Cancer 2011; 117: 938. 14. Denzinger S, Burger M, Walter B et al: Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acidinduced fluorescence diagnosis: 8-year results of prospective randomized study. Urology 2007; 69: 675. 15. Babjuk M, Soukup V, Petrik R et al: 5-Aminolaevulinic acid-induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer. BJU Int 2005; 96: 798.
Cost-Effectiveness of Fluorescent Cystoscopy for Noninvasive Papillary Tumors THE initial resection of bladder tumors is inadequate in many patients, and the recurrence rates at first followup are as high as 20% for solitary tumors and 45% for multiple tumors.1 Use of white light (WL) cystoscopy has been shown to miss some bladder cancers, especially areas of dysplasia and carcinoma in situ. As such, fluorescence based photodynamic diagnostic (PDD) techniques have been developed to take advantage of the fact that photoactive compounds accumulate in neoplastic tissue compared to normal tissue and fluoresce red under blue light illumination.2 Initially ␦-aminolevulinic acid (5-ALA) was used for PDD but it was limited by low bioavailability and heterogeneous distribution in neoplastic tissues.3 Subsequently more potent lipophilic derivates such as hexyl aminolevulinate (HAL) were developed which increased the amount of photoactive porphyrins produced within a shorter period at lower drug doses, allowing significantly shorter bladder instillation time and better cystoscopic examination.4 Two phase III multicenter studies of patients with noninvasive bladder cancer revealed increased detection rates for dysplasia, Ta and T1 tumors.5,6 Although these results were considered sufficient for the approval and adoption of HAL fluorescent cystoscopy in Europe, the Food and Drug Administration required for its approval a strict prospective trial that demonstrated a reduction in bladder recurrence when fluorescent transurethral resection of bladder tumors (TURBT) was performed compared to WL TURBT.7 Should PDD be used for every TURBT? What is the cost-effectiveness of using fluorescent TURBT given the costs of acquiring the instruments needed and the ongoing cost of HAL as well as indirect costs associated with instillation? We debate the cost-effectiveness of PDD for the management of noninvasive bladder cancer.
PRO Bladder cancer with its lifelong monitoring and multiple recurrences is one of the most costly malignancies to manage from diagnosis to death. Two-thirds 0022-5347/12/1875-1537/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
of the overall costs are related to TURBT for nonmuscle invasive bladder cancer. Thus, reducing the number of TURBTs required is likely to have the most significant impact on cost reduction. The initial observations that fluorescent cystoscopy can be effective in detecting flat lesions missed by standard WL cystoscopy have been confirmed by many studies, including the Food and Drug Administration registration randomized TURBT trial which showed that of 41 patients with carcinoma in situ found by HAL cystoscopy 13 (32%) did not have carcinoma in situ detected by WL (p ⬍0.0001).8 Perhaps more surprising and directly related to the topic of this debate is the finding in most studies that even expert surgeons using optimal WL modern instruments will miss 1 or more papillary tumors in approximately 20% of cases. In the Food and Drug Administration trial of WL vs HAL TURBT, which included several investigators newly trained in the technique, at least 1 tumor was seen only with fluorescence in 16% of patients (p⫽0.001).7 Resection of these additional tumors resulted in a 16% relative reduction in recurrence at 9 months. With longer followup (median 55 months) HAL TURBT had a longer time to first recurrence of 16.4 months vs 9.6 months for WL (p⫽0.04).8 Moreover, 20% more patients (31.8% vs 38%) had no recurrence in more than 4 years. European studies from early adopters provided evidence that, although PDD requires investment in equipment and is associated with ongoing costs for the purchase of the fluorescent agent, this higher overall cost is recouped via greater diagnostic accuracy, a lower rate of disease recurrence and reduced overall disease management expenditures.9 In a study of 191 patients with nonmuscle invasive bladder cancer randomized to initial WL vs PDD TURBT, a median followup of 85 months and observed recurrence rate of 46% the conclusion was that PDD related expenditures were reimbursed within the first year. However, the potential of additional benefit of repeated use of HAL TURBT in patients with recurrence cannot be assessed by existing literature based on a single initial use of the technique. Of 327 Vol. 187, 1537-1539, May 2012 Printed in U.S.A. DOI:10.1016/j.juro.2012.02.2563
www.jurology.com
1537
1538
OPPOSING VIEWS
patients with recurrent bladder cancer at baseline the absolute reduction of recurrence was 11.2% (50.6% for HAL vs 61.8% for WL).7 This observation suggests that past the cost neutral initial year, use of HAL TURBT for all subsequent recurrences will result in significant cumulative cost savings. An immediate intravesical, single dose instillation of mitomycin C (MMC) after TURBT is currently recommended in all guidelines because it delays recurrence in 15% to 20% of cases. Nevertheless, it is wellknown that a majority of urologists in the United States and Europe do not prescribe perioperative MMC for a number of reasons including operating room strict guidelines on administration of chemotherapy, lack of experience of nursing personnel in handling chemotherapy drugs, and concern about deep resection and delayed healing often noted several months after TURBT and MMC. Also, not all remaining papillary tumors will be sensitive to chemotherapy while TURBT will effectively eliminate those that have been visualized. HAL TURBT has little toxicity and can be used in all patients. It helps the surgeons perform a more complete resection, the procedure can be learned rapidly and the instrumentation can also be used for routine standard WL cystoscopies. Could the use of post-TURBT MMC outweigh the benefits of HAL TURBT? This question has been recently addressed in a single institution trial that randomized patients to WL vs HAL TURBT with all patients receiving perioperative MMC.10 A 28.5% risk reduction of tumor recurrence was noted in the HAL TURBT group with a 2-year rate of 32.5% vs 45.6% for WL. Clearly HAL TURBT for all nonmuscle invasive bladder cancer will result in better patient care and significant overall cost reduction for the lifelong management of this disease. Moreover, it will result in significant improvement in quality of life as well as other cost benefits to the patient, such as societal advantages of gained wages and productivity owing to decreases in disease recurrence and need for surgery. Yves Fradet Centre Hospitalier Universitaire de Quebec Quebec, Canada
CON The cost of a new technology is relatively objective. There are costs of necessary equipment, which in this case includes PDD scopes and D light units with cables and monitors. Such capital equipment is reusable for many cases and usually amortized over 7 years. Cost estimates obtained from Karl Storz Inc. for all capital equipment is approximately $90,000. The cost per case for the capital equipment will
depend on volume. A relatively high volume practice may perform 100 TURBTs a year resulting in a cost per case of approximately $128. There is also cost of Hexvix® used in each case with the price per Cysview® kit of $600. As such each case would have a direct cost of around $728. The majority of the cost of PDD is from instillation of Hexvix and cost of capital equipment is a relatively small percentage of overall cost. Based on this fact, even a much higher case volume will not dramatically reduce the cost of PDD. The direct cost calculated of $728 does not include the cost of nursing for instilling the Hexvix or the cost to the facility of housing a patient for the hour required to have the Hexvix instilled in the bladder. The cost of TURBT has been estimated around $3,800,11 which results in a cost ratio of about 5:1. In other words, 1 TURBT would have to be avoided for every 5 fluorescent cystoscopy procedures performed to achieve cost equivalence. Obviously this ratio can vary depending on the cost of TURBT at each institution which can vary, and potential indirect costs associated with loss of work and potential complications. The issue of efficiency is probably the more important question to address since one might consider the added expense to be acceptable if the benefits are great. One can agree that meaningful outcomes for bladder cancer include survival, progression and recurrence in that order. To my knowledge, no analyses thus far have demonstrated improved survival due to PDD. Several studies have evaluated the benefit of PDD in regard to progression but none has found a benefit.7,12–14 It should be noted that progression was not the primary end point of any study to date. Nevertheless, the main potential benefit identified is the risk of recurrence. Several single center studies have noted reduced recurrence rates using 5-ALA PDD compared to WL.14,15 However, 2 prospective randomized studies revealed no significant differences between the 5-ALA and WL groups with regard to recurrence-free and progression-free survival rates.12,13 Hexvix has the purported advantage over ALA of producing an increased amount of photoactive porphyrins within a shorter period at lower drug doses, allowing significantly shorter bladder instillation time and better cystoscopic examination.4 A prospective, randomized multicenter study enrolled 814 patients suspected of having bladder cancer at increased risk for recurrence based on more than 1 initial or recurrent bladder tumor within 12 months of a previous bladder tumor.7 During the 9-month followup (intent to treat) tumor recurred in 128 of 271 patients (47%) in the fluorescence group and 157 of 280 (56%) in the WL group (p⫽0.026) with a relative reduction in recurrence of 16%. The recur-
OPPOSING VIEWS
rence in low grade Ta was 45.4% vs 55.4% in the PDD and WL groups, respectively (p⫽0.02). However, in the patients with Ta high grade and T1 tumors the recurrence was 54.8% vs 56.6% in the PDD and WL groups, respectively (p⫽0.48). As such, the only demonstrated benefit is in reduction of recurrent low grade noninvasive tumors. This study was limited to higher risk patients, and so whether such a benefit will also be present in patients with typical risk of recurrence remains to be seen. The study was also optimized for performance of PDD by excluding patients with hematuria and those who received bacillus Calmette-Guérin or chemotherapy within 3 months. Furthermore, the first 5 patients enrolled in the study were excluded to reduce issues with learning curves. Taken together, the benefits of PDD with HAL appear minimal with a number needed to treat of more than 6 to
1539
prevent 1 TURBT in a patient with a low grade noninvasive tumor. This rate exceeds the threshold of cost-effectiveness based on the aforementioned discussion of cost. There are also practical needs that make PDD difficult, including patients must present an hour earlier for instillation, someone is required to instill the Hexvix and a surgeon must be present to evaluate the bladder using WL and PDD. In conclusion, for patients with noninvasive papillary tumors, the use of PDD has practical limitations, limited efficacy in reducing recurrence that is confined to low grade tumors and costs that exceed benefits. Yair Lotan Department of Urology University of Texas Southwestern Medical Center Dallas, Texas
REFERENCES 1. Brausi M, Collette L, Kurth K et al: Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol 2002; 41: 523. 2. Krieg RC, Messmann H, Rauch J et al: Metabolic characterization of tumor cell-specific protoporphyrin IX accumulation after exposure to 5-aminolevulinic acid in human colonic cells. Photochem Photobiol 2002; 76: 518. 3. Witjes JA and Douglass J: The role of hexaminolevulinate fluorescence cystoscopy in bladder cancer. Nat Clin Pract Urol 2007; 4: 542. 4. Jichlinski P, Guillou L, Karlsen SJ et al: Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer—a multicenter study. J Urol 2003; 170: 226. 5. Grossman HB, Gomella L, Fradet Y et al: A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. J Urol 2007; 178: 62.
6. Jocham D, Witjes F, Wagner S et al: Improved detection and treatment of bladder cancer using hexaminolevulinate imaging: a prospective, phase III multicenter study. J Urol 2005; 174: 862. 7. Stenzl A, Burger M, Fradet Y et al: Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. J Urol 2010; 184: 1907. 8. Grossman HB, Natale RB, Tangen CM et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859. 9. Zaak D, Wieland WF, Stief CG et al: Routine use of photodynamic diagnosis of bladder cancer: practical and economic issues. Eur Urol, suppl., 2008; 7: 536. 10. Geavlete B, Multescu R, Georgescu D et al: Treatment changes and long-term recurrence rates after hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non-muscle-invasive bladder cancer (NMIBC)? BJU Int 2012; 109: 549. 11. Lotan Y, Svatek RS and Sagalowsky AI: Should we screen for bladder cancer in a high-risk pop-
ulation? A cost per life-year saved analysis. Cancer 2006; 107: 982. 12. Schumacher MC, Holmang S, Davidsson T et al: Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic acid under visible and fluorescent light: results of a prospective, randomised, multicentre study. Eur Urol 2010; 57: 293. 13. Stenzl A, Penkoff H, Dajc-Sommerer E et al: Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy: a multicenter randomized, double-blind, placebo-controlled trial. Cancer 2011; 117: 938. 14. Denzinger S, Burger M, Walter B et al: Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acidinduced fluorescence diagnosis: 8-year results of prospective randomized study. Urology 2007; 69: 675. 15. Babjuk M, Soukup V, Petrik R et al: 5-Aminolaevulinic acid-induced fluorescence cystoscopy during transurethral resection reduces the risk of recurrence in stage Ta/T1 bladder cancer. BJU Int 2005; 96: 798.