Diagnostik und Therapie des nicht muskelinvasiven Harnblasenkarzinoms – State of the Art

Zusammenfassung

80 % aller diagnostizierten Harnblasenkarzinome sind auf die Mukosa begrenzt und werden als nicht muskelinvasive Blasenkarzinome bezeichnet (NMIBC) (Ta, T1, Cis). Bei diesen liegen offenbar unterschiedliche molekulare Entstehungspfade mit völlig unterschiedlicher Prognose vor. Standardbehandlung ist in den meisten Fällen die transurethrale Resektion (TUR) mit Re-TUR und adjuvanter intravesikaler Chemotherapie oder Immuntherapie. Verschiedene, mit der Diagnostik assoziierte Entwicklungen wie der Nutzen der neuen WHO-Klassifikation, der Benefit der photodynamischen Diagnostik (PDD) und des Narrow band imagings (NBI) sowie der klinische Wert von Tumormarkern werden diskutiert. Die Therapie von NMIBC beinhaltet die monopolare oder bipolare TUR. Nachfolgend wird eine Instillations-therapie in Abhängigkeit der Risikostratifikation empfohlen. Vielversprechende neue Substanzen und instrumentell-assistierte Verfahren wie Thermochemotherapie und EMDA werden diskutiert. Die zusätzliche PDD-vermittelte Information führt offenbar zu einer besseren Diagnose und Behandlung aller NMIBC. Das Routine-Urogramm scheint unnötig zu sein. Der Wert von diagnostischen Urintests ist nach wie vor ungenügend definiert. Einige neue Aspekte zu prognostischen Markern werden präsentiert. Während eine Chemo-Frühinstillation bei Low-Risk-Tumoren ausreichend zu sein scheint und BCG die Therapie der Wahl bei High-Risk-Tumoren darstellt, ist die Literatur zur Behandlung des Intermediate-Risk-Tumors weiterhin uneinheitlich. Besonders problematisch sind Tumorrezidive nach intravesikaler Therapie von Intermediate und High-Risk Patienten. Die Frage der optimalen Therapie insbesondere bei BCG-Versagern aber auch bei T1-High-Grade-Tumoren wird diskutiert. Die frühe Zystektomie stellt eine sichere Option dar aber auch andere Verfahren sind alternativ möglich. 

Abstract

Around 80 % of newly diagnosed bladder cancers are confined to the mucosa and staged as non-muscle-invasive bladder cancer (NMIBC) (Ta, T1, Cis). These tumours appear to segregate into different main molecular pathways with extremely variable prognoses. The standard treatment for NMIBC is transurethral tumour resection (TUR) with Re-TUR and adjuvant intravesical chemotherapy or intravesical immunotherapy in most cases. Several developments associated with diagnosis such as the usefulness of the new WHO grading classification, the benefit of photodynamic diagnosis (PDD) or narrow band imaging (NBI), as well as the clinical value of tumour markers are discussed. Therapy for NMIBC includes monopolar or bipolar TUR. Subsequent instillation therapy is given according to the risk stratification. Several promising new substances as well as device-assisted procedures such as thermochemotherapy or EMDA are discussed. The additional information gained by PDD obviously leads to a better diagnosis and treatment of all NMIBC. Routine IVU does not seem necessary. The value of diagnostic urine tests is still insufficiently defined. Several new aspects concerning prognostic markers are presented. While early chemotherapy instillation seems sufficient in low-risk tumours and BCG is the standard treatment for high-risk disease, the literature about treatment of intermediate risk tumors is still conflicting. Especially problematic is the case of recurrent disease after intravesical therapy in intermediate and high-risk patients. The question as to what has to be done in failure after BCG is discussed. Cystectomy is a safe option but other approaches are potential alternatives. 

Schlüsselwörter

Harnblasenkarzinom - Diagnostik - Therapie - Marker - Instillation

Key words

bladder cancer - diagnosis - therapy - markers - instillation

Literatur

• 1 Jemal A, Siegel R, Ward E et al. Cancer statistics, 2009 CA.  Cancer J Clin. 2009;  59 225-249
• 2 http://www.rki.de . 
• 3 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 2 596 patients from seven EORTC trials.  Eur Urol. 2006;  49 466-475
• 4 Burger M, van der Aa M NM, van Oers J MM et al. Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study.  Eur Urol. 2008;  54 835-844
• 5 Williams S G, Stein J P. Molecular pathways in bladder cancer.  Urol Res. 2004;  32 373-385
• 6 Wolff E M, Liang G, Jones P A. Mechanisms of disease: genetic and epi­genetic alterations that drive bladder cancer.  Nat Clin Pract Urol. 2005;  2 502-510
• 7 Knowles M A. Molecular pathogenesis of bladder cancer.  Int J Clin Oncol. 2008;  13 287-297
• 8 Goessl C, Knispel H H, Miller K et al. Is routine excretory urography necessary at first diagnosis of bladder cancer?.  J Urol. 1997;  157 480-481
• 9 Holmang S, Hedelin H, Anderstrom C et al. Long-term followup of a bladder carcinoma cohort: routine followup urography is not necessary.  J Urol. 1998;  160 45-48
• 10 Kirkali Z, Chan T, Manoharan M et al. Bladder cancer: epidemiology, staging and grading, and diagnosis.  Urology. 2005;  66 4-34
• 11 Oosterlinck W, Solsona E, Akaza H et al. Low-grade Ta urothelial carcinoma of the bladder.  Urology. 2005;  66 75-89
• 12 Sauter G, Algaba F, Amin M et al. Non-invasive urothelial neoplasias. WHO classification of non-invasive papillary urothelial tumors. In: Eble JN, Sauter G, Epstein JI, Sesterhenn I, eds. World Health Organi­zation classification of tumors. Pathology and genetics: Tumors of the urinary system and male genital organs. Lyon: IARCC Press; 2004: 89–157
• 13 Jichlinski P, Leisinger H J. Fluorescence cystoscopy in the management of bladder cancer: a help for the urologist!.  Urol Int. 2005;  74 97-101
• 14 Burger M, Stief C G, Zaak D et al. Hexaminolaevulinate is equal to 5-Aminolaevilinic Acid concerning residual tumour and recurrence rate following photodynamic diagnostic assisted transurethral resection of bladder tumours.  Urology. 2009;  74 1282-1286
• 15 Babjuk M, Oosterlinck W, Sylvester R et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder.  Eur Urol. 2008;  54 303-314
• 16 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. 2009;  (epub ahead of print)
• 17 Herr H W, Donat S M. A comparison of white-light cystoscopy and narrow-band imaging cystoscopy to detect bladder tumour recurrences.  BJU Int. 2008;  102 1111-1114
• 18 Bryan R T, Billingham L J, Wallace D M. Narrow-band imaging flexible ­cystoscopy in the detection of recurrent urothelial cancer of the bladder.  BJU Int. 2008;  101 702-705
• 19 Cauberg E C, Kloen S, Visser M et al. Narrow band imaging cystoscopy improves the detection of non-muscle-invasive bladder cancer.  Urol­ogy. 2010;  (Epub ahead of print)
• 20 Karakiewicz P I, Benayoun S, Zippe C et al. Institutional variability in the accuracy of urinary cytology for predicting recurrence of transitional cell carcinoma of the bladder.  BJU Int. 2006;  97 997-1001
• 21 Kausch I, Böhle A. Bladder cancer. II. Molecular aspects and diagnosis.  Eur Urol. 2001;  39 498-506
• 22 Van Rhijn B W, van der Poel H G, van der Kwast T H. Urine markers for bladder cancer surveillance: a systematic review.  Eur Urol. 2005;  47 736-748
• 23 Shariat S F, Karam J A, Lotan Y et al. Critical evaluation of urinary mark­ers for bladder cancer detection and monitoring.  Reviews in Urol. 2008;  10 120-135
• 24 Lotan Y, Svatek R S, Sagalowsky A I. Should we screen for bladder cancer in a high-risk population?: A cost per life-year saved analysis.  Cancer. 2006;  107 982-990
• 25 Vriesema J L, Poucki M H, Kiemeney L A. Patient opinion of urinary tests versus flexible urethrocystoscopy in follow-up examination for superficial bladder cancer: a utility analysis.  Urology. 2000;  56 793-797
• 26 Habuchi T, Marberger M, Droller M J et al. Prognostic markers for bladder cancer: international consensus panel on bladder tumor markers.  Urology. 2005;  66 64-74
• 27 Bryan R T, Zeegers M P, James N D et al. Biomarkers in bladder cancer.  BJU Int. 2009;  105 608-613
• 28 Karam J A, Lotan Y, Karakiewicz P l et al. Use of combined apoptosis ­biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy.  Lancet Oncology. 2007;  8 128-136
• 29 Margulis V, Shariat S F, Ashfaq R et al. Ki-67 is an independent predictor of bladder cancer outcome in patients treated with radical cystectomy for organ-confined disease.  Clin Cancer Res. 2006;  12 7369-7373
• 30 Margulis V, Lotan Y, Karakiewicz P I et al. Multi-institutional validation of the predictive value of Ki-67 labeling index in patients with urinary bladder cancer.  JNCI. 2009;  101 114-119
• 31 Shariat S F, Svatek R S, Tilki D et al. International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy.  BJU Int. 2010;  105 1402-1412
• 32 Riley R D, Sauerbrei W, Altman D G. Prognostic markers in cancer: the evolution of evidence from single studies to meta-analysis, and beyond.  Br J Cancer. 2009;  100 1219-1229
• 33 Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J et al. Primary superficial bladder cancer risk groups according to progression, mortality and recurrence.  J Urol. 2000;  164 680-684
• 34 Sylvester R J, van der Meijden A PM, 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 2 596 patients from seven EORTC trials.  Eur Urol. 2006;  49 466-477
• 35 Fernandez-Gomez J, Solsona E, Unda M et al. Prognostic factors in ­patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: multivariate analysis of data from four randomized CUETO trials.  Eur Urol. 2008;  53 992-1001
• 36 Fernandez-Gomez J, Madero R, Solsona E et al. Predicting nonmuscle ­invasive bladder cancer recurrence and progression in patients with bacillus Calmette-Guerin:the CUETO scoring model.  J Urol. 2009;  182 2195-2203
• 37 Sylvester R J, Oosterlinck W, van der Meijden A P. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials.  J Urol. 2004;  171 2186-2190
• 38 Bouffioux C, Kurth K H, Bono A et al. Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 Euro­pean Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genito­urinary Group.  J Urol. 1995;  153 934-941
• 39 Berrum-Svennung I, Granfors T, Jahnson S et al. A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences.  J Urol. 2008;  179 101-105
• 40 Gudjonson S, Adell L, Merdasa F et al. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomized multicentre study.  Eur Urol. 2009;  55 773-780
• 41 Cai T, Nesi G, Tinacci G et al. Can early single dose instillation of epi­rubicin improve bacillus Calmette-Guerin efficacy in patients with nonmuscle invasive high risk bladder cancer? Results from a prospective, randomized, double-blind controlled study.  J Urol. 2008;  180 110-115
• 42 Hendricksen K, Witjes W P, Idema J G et al. Comparison of three schedules of intravesical epirubicin in patients with non-muscle-invasive bladder cancer.  Eur Urol. 2008;  53 984-991
• 43 Sylvester R J, Oosterlinck W. An immediate instillation after transurethral resection of bladder tumor in non-muscle-invasive bladder cancer: Has the evidence changed?.  Eur Urol. 2009;  56 43-45
• 44 Sylvester R J, Oosterlinck W, Witjes J A. The schedule and duration of ­intravesical chemotherapy in patients with non-muscle-invasive bladder cancer: a systematic review of the published results of randomized clinical trials.  Eur Urol. 2008;  53 709-719
• 45 Au J L, Badalament R A, Wientjes M G et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.  JNCI. 2001;  93 597-604
• 46 Böhle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer.  J Urol. 2003;  170 964-969
• 47 Martinez-Pineiro J A, Martinez-Pineiro L, Solsona E et al. Has a 3-fold ­decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Cis bladder tumors than the standard dose? Results of a prospective randomized trial.  J Urol. 2005;  174 1242-1247
• 48 Colombel M, Saint F, Chopin D et al. The effect of ofloxacin on bacillus Calmette-Guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study.  J Urol. 2006;  176 935-939
• 49 Shelley M D, Mason M D, Kynaston H. Intravesical therapy for superficial bladder cancer: A systematic review of randomised trials and meta-analyses.  Cancer Treatment Rev. 2010;  36 195-205
• 50 de Reijke T M, Kurth K H, Sylvester R J European Organization for the Research and Treatment of Cancer-Genito-Urinary Group et al.,. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer-Genito-Urinary Group Phase III Trial (30906).  J Urol. 2005;  173 405-409
• 51 Järvinen R, Kaasinen E, Sankila A et al. Long-term efficacy of main­tenance bacillus Calmette Guerin versus maintenance mitomycin c ­instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up.  Eur Urol. 2009;  56 260-265
• 52 Sylvester R J, van der Meijden A P, Lamm D L. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials.  J Urol. 2002;  168 1964-1970
• 53 Böhle A, Bock P R. Intravesical bacillus Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression.  Urology. 2004;  63 682-687
• 54 Pawinski A, Sylvester R, Kurth K H et al. A combined analysis of Euro­pean Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of Ta T1 bladder cancer. EORTC Cooperative group and the Medical Research Council Working Party on superficial bladder cancer.  J Urol. 1996;  156 1934-1941
• 55 Malmström P -U, Sylvester R J, Crawford D E et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus Calmette Guerin for non-muscle-invasive bladder cancer.  Eur Urol. 2009;  56 247-256
• 56 Hendricksen K, van der Heijden A G, Cornel E B et al. Two-year follow-up of the phase II marker lesion study of intravesical apaziquone for patients with non-muscle invasive bladder cancer.  World J Urol. 2009;  176 337-342
• 57 Böhle A, Leyh H, Frei C et al. Single postoperative instillation of gem­citabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. S274 Study Group.  Eur Urol. 2009;  56 495-503
• 58 Porena M, Del Zingaro M, Lazzeri M et al. Bacillus Calmette-Guérin versus gemcitabine for intravesical therapy in high-risk superficial bladder cancer: a randomised prospective study.  Urol Int. 2010;  84 23-27
• 59 Addeo R, Caraglia M, Bellini S et al. Randomized phase III trial on gem­citabine versus mitomycin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance.  J Clin Oncol. 2010;  28 543-548
• 60 Di Lorenzo G, Perdonà S, Damiano R et al. Gemcitabine versus bacille Calmette-Guérin after initial bacille Calmette-Guérin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial.  Cancer. 2010;  116 1893-1900
• 61 Joudi F N, Smith B J, O'Donnell M A. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alpha-B for reducing recurrence of superficial bladder cancer.  Urol Oncol. 2006;  24 344-348
• 62 Lingnau A, Steiner U, Kurzidim H et al. Phase I dose-escalation study of intravesical instillation of antisense oligonucleotide FFC15-01 against Ki-67 in patients with superficial bladder cancer.  Debates on bladder cancer. 2010;  2 1-6
• 63 Jocham D, Windeler J, Jensen K et al. BCG versus Photodynamische Therapie (PDT) beim nicht muskelinvasiven Harnblasenkarzinom – eine multizentrische Phase-III-Studie.  Akt Urol. 2009;  40 91-99
• 64 van der Heijden A G, Kiemeney L A, Gofrit O N et al. Preliminary European results of local microwave hyperthermia and chemotherapy treatment in intermediate or high risk superficial transitional cell carcinoma of the bladder.  Eur Urol. 2004;  46 65-71
• 65 Colombo R, Da Pozzo L F, Salonia A et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyper­thermia for prophylaxis of recurrence of superficial transitional cell carcinoma.  J Clin Oncol. 2003;  21 4270-4276
• 66 Witjes A, Hendricksen K, Gofrit O et al. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European synergo working party.  World J Urol. 2009;  27 319-324
• 67 Di Stasi S M, Gianpantoni A, Stephen R L et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study.  J Urol. 2003;  170 777-782
• 68 Di Stasi S M, Storti L, Giurioli A et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomized controlled trial.  Lancet Oncol. 2006;  7 43-51
• 69 Di Stasi S M, Storti L, Giurioli A. Single immediate preoperative instillation of electromotive mitomycin-C plus transurethral resection versus transurethral resection alone versus transurethral resection plus immediate mitomycin-C fot pTa bladder tumors: long-term results of a prospective randomized trial.  J Urol. 2008;  179 (S 4) 585
• 70 Lamm D, Colombel M, Persad R et al. Clinical practice recommendations for the management of non-muscle invasive bladder cancer.  Eur Urol Suppl. 2008;  7 651-666
• 71 Schrier B P, Hollander M P, van Rhijn B W et al. Prognosis of muscle-invasive bladder cancer: difference between primary and progressive tumours and implications for therapy.  Eur Urol.. 2004;  45 292-296
• 72 Guzzo T J, Magheli A, Bivalacqua T J. Pathological upstaging during radical cystectomy is associated with worse recurrence-free survival in ­patients with bacillus Calmette-Guerin-refractory bladder cancer.  Urol­ogy. 2009;  74 1276-1280
• 73 Nieder A M, Brausi M, Lamm D et al. Management of stage T1 tumors of the bladder: international consensus panel.  Urology. 2005;  66 (6 Suppl 1) 108-125
• 74 Fritsche H M, Burger M, Svatek R S et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with ­radical cystectomy: results from an international cohort.  Eur Urol. 2010;  57 300-309
• 75 Denzinger S, Burger M, Fritsche H M et al. Bladder preservation or initial cystectomy in T1G3 bladder cancer: which parameters help in therapeutic decision-making?.  Akt Urol. 2008;  39 58-61
• 76 Denzinger S, Fritsche H M, Otto W et al. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach?.  Eur Urol. 2007;  53 146-152
• 77 Stanislaus P, Zaak D, Stadler T et al. Photodynamic diagnosis in patients with T1G3 bladder cancer: influence on recurrence rate.  World J Urol. 2010;  28 407-411