Platinum Priority – Review – Bladder Cancer Editorial by T.R. Leyshon Griffiths and Roger C. Kockelbergh on pp. 872–873 of this issue| Volume 66, ISSUE 5, P863-871, November 01, 2014

Clinical and Cost Effectiveness of Hexaminolevulinate-guided Blue-light Cystoscopy: Evidence Review and Updated Expert Recommendations



      Non–muscle-invasive bladder cancer (NMIBC) is associated with a high recurrence risk, partly because of the persistence of lesions following transurethral resection of bladder tumour (TURBT) due to the presence of multiple lesions and the difficulty in identifying the exact extent and location of tumours using standard white-light cystoscopy (WLC). Hexaminolevulinate (HAL) is an optical-imaging agent used with blue-light cystoscopy (BLC) in NMIBC diagnosis. Increasing evidence from long-term follow-up confirms the benefits of BLC over WLC in terms of increased detection and reduced recurrence rates.


      To provide updated expert guidance on the optimal use of HAL-guided cystoscopy in clinical practice to improve management of patients with NMIBC, based on a review of the most recent data on clinical and cost effectiveness and expert input.

      Evidence acquisition

      PubMed and conference searches, supplemented by personal experience.

      Evidence synthesis

      Based on published data, it is recommended that BLC be used for all patients at initial TURBT to increase lesion detection and improve resection quality, thereby reducing recurrence and improving outcomes for patients. BLC is particularly useful in patients with abnormal urine cytology but no evidence of lesions on WLC, as it can detect carcinoma in situ that is difficult to visualise on WLC. In addition, personal experience of the authors indicates that HAL-guided BLC can be used as part of routine inpatient cystoscopic assessment following initial TURBT to confirm the efficacy of treatment and to identify any previously missed or recurrent tumours. Health economic modelling indicates that the use of HAL to assist primary TURBT is no more expensive than WLC alone and will result in improved quality-adjusted life-years and reduced costs over time.


      HAL-guided BLC is a clinically effective and cost-effective tool for improving NMIBC detection and management, thereby reducing the burden of disease for patients and the health care system.

      Patient summary

      Blue-light cystoscopy (BLC) helps the urologist identify bladder tumours that may be difficult to see using standard white-light cystoscopy (WLC). As a result, the amount of tumour that is surgically removed is increased, and the risk of tumour recurrence is reduced. Although use of BLC means that the initial operation costs more than it would if only WLC were used, over time the total costs of managing bladder cancer are reduced because patients do not need as many additional operations for recurrent tumours.


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      1. International Agency for Research on Cancer. Globocan 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Accessed February 2014.

        • Sylvester R.J.
        • van der Meijden A.P.
        • Oosterlinck W.
        • et al.
        Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials.
        Eur Urol. 2006; 49: 466-475
        • Babjuk M.
        • Burger M.
        • Zigeuner R.
        • et al.
        EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013.
        Eur Urol. 2013; 64: 639-653
        • Sievert K.D.
        • Amend B.
        • Nagele U.
        • et al.
        Economic aspects of bladder cancer: what are the benefits and costs?.
        World J Urol. 2009; 27: 295-300
        • Herr H.W.
        • Donat S.M.
        Quality control in transurethral resection of bladder tumours.
        BJU Int. 2008; 102: 1242-1246
        • Ray E.R.
        • O’Brien T.S.
        Approaches to reducing recurrence in superficial bladder cancer.
        Eur Urol Rev. 2005; : 1-6
        • Kausch I.
        • Sommerauer M.
        • Montorsi F.
        • et al.
        Fluoreszenzdiagnostik bei Patienten mit nicht muskelinvasivem Harnblasenkarzinom: Ergebnisse einer Metaanalyse.
        Aktuelle Urol. 2010; 41: 171-177
        • Kausch I.
        • Sommerauer M.
        • Montorsi F.
        • et al.
        Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies.
        Eur Urol. 2010; 57: 595-606
        • Isfoss B.L.
        The sensitivity of fluorescent-light cystoscopy for the detection of carcinoma in situ (CIS) of the bladder: a meta-analysis with comments on gold standard.
        BJU Int. 2011; 108: 1703-1707
        • Lerner S.P.
        • Liu H.
        • Wu M.F.
        • Thomas Y.K.
        • Witjes J.A.
        Fluorescence and white light cystoscopy for detection of carcinoma in situ of the urinary bladder.
        Urol Oncol. 2012; 30: 285-289
        • Shen P.
        • Yang J.
        • Wei W.
        • et al.
        Effects of fluorescent light-guided transurethral resection on non-muscle-invasive bladder cancer: a systematic review and meta-analysis.
        BJU Int. 2012; 110: E209-E215
        • Yuan H.
        • Qiu J.
        • Liu L.
        • et al.
        Therapeutic outcome of fluorescence cystoscopy guided transurethral resection in patients with non-muscle invasive bladder cancer: a meta-analysis of randomized controlled trials.
        PLoS ONE. 2013; 8: e74142
        • Burger M.
        • Grossman H.B.
        • Droller M.
        • et al.
        Photodynamic diagnosis of non-muscle invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis.
        Eur Urol Suppl. 2013; 12: e577
        • Burger M.
        • Grossman H.B.
        • Droller M.
        • et al.
        Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data.
        Eur Urol. 2013; 64: 846-854
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Rink M.
        • Babjuk M.
        • Catto J.W.F.
        • et al.
        Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: a critical review of the current literature.
        Eur Urol. 2013; 64: 624-638
      2. Scottish Intercollegiate Guidelines Network Management of transitional cell carcinoma of the bladder: a national clinical guideline. SIGN 85. Edinburgh, UK: SIGN; 2005.

      3. Integraal Kankercentrum Nederland. Urotheelcarcinoom van de blaas. Accessed February 2014.

        • Kamat A.M.
        • Hegarty P.K.
        • Gee J.R.
        • et al.
        ICUD-EAU International Consultation on Bladder Cancer 2012: screening, diagnosis, and molecular markers.
        Eur Urol. 2013; 63: 4-15
      4. Multi-disciplinary team (MDT) guidance for managing bladder cancer, ed 2. British Association of Urological Surgeons Web site.

        • Pfister C.
        • Roupret M.
        • Neuzillet Y.
        • et al.
        Recommandations en onco-urologie 2013 du CCAFU: tumeur urothéliales.
        Prog Urol. 2013; 23: S105-S125
      5. Associazione Italiana di Oncologia Medica (AIOM). Linee guida: carcinoma della vescica.,333,1. Accessed February 2014.

        • Stenzl A.
        • Jocham D.
        • Jichlinski P.
        • et al.
        Photodynamische Diagnostik im Harntrakt: Konsensusempfehlungen des Arbeitskreises Onkologie der Deutschen Gesellschaft für Urologie.
        Urologe A. 2008; 47: 982-987
        • Witjes J.A.
        • Redorta J.P.
        • Jacqmin D.
        • et al.
        Hexaminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: review of the evidence and recommendations.
        Eur Urol. 2010; 57: 607-614
        • Bunce C.
        • Ayres B.E.
        • Griffiths T.R.
        • et al.
        The role of hexylaminolaevulinate in the diagnosis and follow-up of non-muscle-invasive bladder cancer.
        BJU Int. 2010; 105: 2-7
        • Malmstrom P.U.
        • Grabe M.
        • Haug E.S.
        • et al.
        Role of hexaminolevulinate-guided fluorescence cystoscopy in bladder cancer: critical analysis of the latest data and European guidance.
        Scand J Urol Nephrol. 2012; 46: 108-116
      6. Agrawal S, Mufti U, Rowland S, Hrouda D, Shamsuddin A. Diagnositic value of photodynamic (PDD) cystoscopy following BCG therapy using intravesical hexaminolavulinate [abstract MP-01.11]. Presented at: Société Internationale d’Urologie annual meeting; September 8–12, 2013; Vancouver, Canada.

        • Draga R.O.
        • Grimbergen M.C.
        • Kok E.T.
        • Jonges T.N.
        • van Swol C.F.
        • Bosch J.L.
        Photodynamic diagnosis (5-aminolevulinic acid) of transitional cell carcinoma after bacillus Calmette-Guerin immunotherapy and mitomycin C intravesical therapy.
        Eur Urol. 2010; 57: 655-660
      7. Pfister C, Descotes JL, Conort P, De La Taille A, Colombel M, Jacqmin D. Usefulness of Hexvix®-guided fluorescence cystocsopy after BCG induction treatment. Poster 193 presented at: European Association of Urology Congress; April 16–20, 2010; Barcelona, Spain.

        • Ray E.R.
        • Chatterton K.
        • Khan M.S.
        • et al.
        Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette-Guerin.
        BJU Int. 2010; 105: 789-794
        • O’Brien T.
        • Ray E.
        • Chatterton K.
        • Khan M.S.
        • Chandra A.
        • Thomas K.
        Prospective randomized trial of hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder cancer.
        BJU Int. 2013; 112: 1096-1104
        • Bertrand J.
        • Soustelle L.
        • Gres P.
        • et al.
        Intérêt de la vidéocystoscopie souple en lumière bleue (+Hexvix®) en consultation pour le diagnostic des tumeurs de vessie.
        Prog Urol. 2012; 22: 172-177
        • Hermann G.G.
        • Mogensen K.
        • Toft B.G.
        • Glenthoj A.
        • Pedersen H.M.
        Outpatient diagnostic of bladder tumours in flexible cystoscopes: evaluation of fluorescence-guided flexible cystoscopy and bladder biopsies.
        Scand J Urol Nephrol. 2012; 46: 31-36
        • Loidl W.
        • Schmidbauer J.
        • Susani M.
        • Marberger M.
        Flexible cystoscopy assisted by hexaminolevulinate induced fluorescence: a new approach for bladder cancer detection and surveillance?.
        Eur Urol. 2005; 47: 323-326
        • Witjes J.A.
        • Moonen P.M.
        • van der Heijden A.G.
        Comparison of hexaminolevulinate based flexible and rigid fluorescence cystoscopy with rigid white light cystoscopy in bladder cancer: results of a prospective phase II study.
        Eur Urol. 2005; 47: 319-322
        • Karl A.
        • Tritschler S.
        • Stanislaus P.
        • et al.
        Positive urine cytology but negative white-light cystoscopy: an indication for fluorescence cystoscopy?.
        BJU Int. 2009; 103: 484-487
        • Loo R.K.
        • Lieberman S.F.
        • Slezak J.M.
        • et al.
        Stratifying risk of urinary tract malignant tumors in patients with asymptomatic microscopic hematuria.
        Mayo Clin Proc. 2013; 88: 129-138
        • Edwards T.J.
        • Dickinson A.J.
        • Natale S.
        • Gosling J.
        • McGrath J.S.
        A prospective analysis of the diagnostic yield resulting from the attendance of 4020 patients at a protocol-driven haematuria clinic.
        BJU Int. 2006; 97: 301-305
        • Grossman H.B.
        • Stenzl A.
        • Fradet Y.
        • et al.
        Long-term decrease in bladder cancer recurrence with hexaminolevulinate enabled fluorescence cystoscopy.
        J Urol. 2012; 188: 58-62
        • Burger M.
        • Zaak D.
        • Stief C.G.
        • et al.
        Photodynamic diagnostics and noninvasive bladder cancer: is it cost-effective in long-term application? A Germany-based cost analysis.
        Eur Urol. 2007; 52: 142-147
        • Burger M.
        • Petschl S.
        • Volkmer B.G.
        Kalkulation einer neuen Untersuchungs- und Behandlungsmethode (NUB): Analyse am Beispiel der PDD-gestützten TUR-B mit Hexaminolävulinsäure.
        Urologe A. 2008; 47: 1239-1244
        • Dindyal S.
        • Nitkunan T.
        • Bunce C.J.
        The economic benefit of photodynamic diagnosis in non-muscle invasive bladder cancer.
        Photodiagnosis Photodyn Ther. 2008; 5: 153-158
        • Malmstrom P.U.
        • Hedelin H.
        • Thomas Y.K.
        • Thompson G.J.
        • Durrant H.
        • Furniss J.
        Fluorescence-guided transurethral resection of bladder cancer using hexaminolevulinate: analysis of health economic impact in Sweden.
        Scand J Urol Nephrol. 2009; 43: 192-198
        • Otto W.
        • Burger M.
        • Fritsche H.M.
        • et al.
        Photodynamic diagnosis for superficial bladder cancer: do all risk-groups profit equally from oncological and economic long-term results?.
        Clin Med Oncol. 2009; 3: 53-58
      8. Bennison C, Tempest M, Marteau F, et al. How investment in a hexaminolevulinate (HAL) technology would be beneficial to patients and healthcare systems in non-muscle invasive bladder cancer (NMIBC) in Italy [abstract S13-3]. Presented at: 10th Health Technology Assessment international annual meeting; June, 2013; Seoul, Korea.

        • Marteau F.
        • Kornowski A.
        • Bennison C.
        • Tempest M.J.
        • Mariappan P.
        • Witjes J.A.
        Cost-effectiveness of the optical imaging agent hexaminolevulinate for patients undergoing initial transurethral resection of non-muscle invasive bladder cancer tumours [abstract 01].
        Eur Urol Suppl. 2013; 12: 125
        • Jacqmin D.
        • Molinier L.
        • Irani J.
        • et al.
        Apport de l’hexylaminolévulinate (Hexvix®) pour la prise en charge des tumeurs de vessie non infiltrant le muscle (TVNIM): résultats de l’étude observationnelle HOPE (Hexvix® Observational Patients Evaluation).
        Prog Urol. 2013; 23: 1123
        • Fritsche H.M.
        • Otto W.
        • Eder F.
        • et al.
        Water-jet-aided transurethral dissection of urothelial carcinoma: a prospective clinical study.
        J Endourol. 2011; 25: 1599-1603
      9. DRKS—Deutsches Register Klinischer Studien (German Clinical Trials Register). DRKS-ID: DRKS00004414. HYbrid knife in bladder cancer resection initially detected by Hexvix based blue-light enhancement (HybridBlue). Accessed February 2014.