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Beyond the Abstract - Developments in intravesical therapy for non-muscle-invasive bladder cancer, Rianne J.M. Lammers, MD, PhD-student and J. Alfred Witjes, MD, PhD

BERKELEY, CA (UroToday.com) - Non-muscle-invasive bladder cancer (NMIBC) is a frequent and heterogeneous disease with varying oncologic outcomes.

The main goal in treating is to prevent recurrences and progression to muscle-invasive disease. Most important variables for recurrence are multiplicity, tumor size and prior recurrence rate. Grade, stage and CIS are the most important variables for progression. These factors have been used by the European Association of Urology (EAU) to divide NMIBC into low-, intermediate- and high-risk groups, based on which subsequent adjuvant therapy can be chosen.1 The disadvantages of these risk tables are related to the inclusion period (1979-1989): a second resection in high-risk patients was not standard, nor were maintenance instillations, and only a few patients received a single immediate postoperative instillation. For this reason Fernandez-Gomez et al. also reported on predictors of progression and recurrence: the Club Urológico Español de Tratamiento Oncológico (CUETO) scoring system.2

 

Conventional intravesical treatment

After a urothelial lesion is detected, the diagnosis and clinical stage is established by transurethral resection of the bladder tumor (TURBT). White light cystoscopy (WLC) is the gold standard for visualization, but is not optimal, as residual superficial tumor is found in up to 20-45% of the patients.3, 4 A means to improve detection of tumors and the quality of the TURBT is fluorescence cystoscopy, or photodynamic diagnosis (PDD). It has been confirmed in several studies that fluorescence-guide resections are more complete than WLC. It is particularly sensitive for detection of CIS, and the procedure is well tolerated. 5,6 In the meta-analysis of Krausch et al., recurrence-free-survival was significantly higher at 12 and 24 months in the PDD groups than in WLC groups.7 However, inflammation, recent TURBT and recent instillations with bacillus Calmette-Guérin (BCG) can cause false-positivity in PDD. 8,9 Another new development which could also improve the quality of TURBT is narrow band imaging (NBI). This technique is based on the phenomenon that the depth of light penetration into the mucosa increases with increasing wavelength. It is a promising new imaging method, but needs validation.10 The standard treatment of all patients with NMIBC after TURBT is an immediate, single, post-operative instillation of chemotherapy. This can reduce the risk for recurrence in the first few years by about 40%.11 Timing of the instillation is believed to be of importance as shown by Kaasinen et al.: they found more than a two-fold risk for recurrence if the first instillation was postponed until the next day.12 In patients with low-risk of recurrence and progression, one immediate single post-operative instillation of chemotherapy may be considered a complete treatment. The need to receive an immediate post-operative instillation for intermediate- and high-risk patients is recently being questioned in several studies. 13,14 We expect that this may lead to a change of the guidelines in the near future. Depending on the risk of recurrence and progression, intravesical chemotherapy or (maintenance) immunotherapy will be used in intermediate- and high-risk patients because it can reduce the short-term risk for recurrence, but the long-term effect is only marginal.15 The optimal schedule and duration of the maintenance chemotherapy remains unknown. Immunotherapy means intravesical instillations with bacillus Calmette-Guérin (BCG), a live attenuated form of Mycobacterium bovis. A cycle of BCG-instillations is advised for intermediate- and high-risk patients.1 BCG is more effective compared to chemotherapy in preventing recurrences, but for that maintenance BCG is needed.16 The reduction of progression rates has recently become a matter of discussion.17 Local side effects such as cystitis and hematuria can be observed in up to 75% of the patients, and is a reason to stop treatment in 15%. Therefore, the advantage of BCG over MMC in intermediate-risk patients has to be balanced against toxicity. In high-risk patients, on the other hand, the superiority of BCG for reducing recurrences is more evident.16,18 Because of toxicity and related treatment discontinuation, several studies compared the standard dose BCG with a reduced dose, and found comparable reduction of the chances on recurrence and progression as the standard dose BCG but less toxicity for the low-dose groups.19,20 Another option to decrease toxicity of BCG is ofloxacin, a fluoroquinolone with tuberculostatic properties.21

 

Development in therapy for non-muscle-invasive bladder cancer

New chemotherapeutic options are intravesical instillations with gemcitabine, apaziquone, taxanes, interferon-α and KLH. Those seem safe in initial studies, but need further evaluation of efficacy. Microwave induced thermo-chemotherapy (or chemo-hyperthermia) and electromotive drug administration both increase the uptake of the therapeutic agent in the urothelium, and seem safe. Most research about chemo-hyperthermia shows that it is also effective. We expect that chemo-hyperthermia might become one of the standard treatment regimens for high-risk patients.

 

Failure of intravesical therapy

  The fate of patients failing intravesical therapy is surprisingly bad. The appropriate management will depend on the type of failure (i.e., chemotherapy or BCG), and the patients’ level of risk. When intravesical chemotherapy fails in low-risk patients, another course of intravesical chemotherapy or BCG-instillations can be given, with good results. For intermediate-risk patients with chemotherapy-failure BCG maintenance or radical cystectomy is advised.22 Treatment of BCG-failure is a big dilemma. At this moment cystectomy still seems to be the best therapy for patients with high-risk or failing BCG-instillations, as the recurrence-free-survival is between 80% and 90% in five years. Furthermore, an early cystectomy is better than a delayed cystectomy, especially in case of CIS.23,24 however, not all patients are willing to undergo cystectomy or are unsuitable for surgery. The use of intravesical chemotherapy (valrubicin, gemcitabine, docetaxel) after BCG-failure is not well studied, but may be an option for patients unsuitable for cystectomy. Therefore, new therapies are needed. Immunotherapy after BCG-failure (BCG+IFN-α) seems promising, but results should be confirmed. Chemo-hyperthermia after BCG-failure seems safe and effective, but long-term results are needed.

 

References:

  1. Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008 August;54(2):303-14.
  2. Fernandez-Gomez J, Madero R, Solsona E et al.. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. J Urol 2009 November;182(5):2195-203.
  3. 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 May;41(5):523-31.
  4. Schulze M, Stotz N, Rassweiler J. Retrospective analysis of transurethral resection, second-look resection, and long-term chemo-metaphylaxis for superficial bladder cancer: indications and efficacy of a differentiated approach. J Endourol 2007 December;21(12):1533-41.
  5. Sievert KD, Kruck S. Hexyl aminolevulinate fluorescence cystoscopy in bladder cancer. Expert Rev Anticancer Ther 2009 August;9(8):1055-63.
  6. 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 July;178(1):62-7.
  7. Kausch I, Sommerauer M, Montorsi F et al.. Fluorescence diagnosis in patients with non-muscle invasive bladder cancer: results of a metaanalysis. Aktuelle Urol 2010 May;41(3):171-7.
  8. Draga RO, Grimbergen MC, Kok ET, Jonges TN, van Swol CF, Bosch JL. Photodynamic diagnosis (5-aminolevulinic acid) of transitional cell carcinoma after bacillus Calmette-Guerin immunotherapy and mitomycin C intravesical therapy. Eur Urol 2010 April;57(4):655-60.
  9. Ray ER, Chatterton K, Khan MS et al.. Hexylaminolaevulinate fluorescence cystoscopy in patients previously treated with intravesical bacille Calmette-Guerin. BJU Int 2010 March;105(6):789-94.
  10. Cauberg EC, Kloen S, Visser M et al.. Narrow band imaging cystoscopy improves the detection of non-muscle-invasive bladder cancer. Urology 2010 March 9.
  11. Sylvester RJ, Oosterlinck W, van der Meijden AP. 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 June;171(6 Pt 1):2186-90, quiz.
  12. Kaasinen E, Rintala E, Hellstrom P et al.. Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma. Eur Urol 2002 August;42(2):167-74.
  13. Berrum-Svennung I, Granfors T, Jahnson S, Boman H, Holmang S. A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences. J Urol 2008 January;179(1):101-5.
  14. Gudjonsson 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 randomised multicentre study. Eur Urol 2009 April;55(4):773-80.
  15. Serretta V, Morgia G, Altieri V et al.. A 1-year maintenance after early adjuvant intravesical chemotherapy has a limited efficacy in preventing recurrence of intermediate risk non-muscle-invasive bladder cancer. BJU Int 2010 January 11.
  16. Gontero P, Bohle A, Malmstrom PU et al.. The role of bacillus Calmette-Guerin in the treatment of non-muscle-invasive bladder cancer. Eur Urol 2010 March;57(3):410-29.
  17. Malmström PU, Sylvester RJ, Crawford DE 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 August;56(2):247-56.
  18. Shelley MD, Mason MD, Kynaston H. Intravesical therapy for superficial bladder cancer: a systematic review of randomised trials and meta-analyses. Cancer Treat Rev 2010 May;36(3):195-205.
  19. Martinez-Pineiro JA, 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 Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 2005 October;174(4 Pt 1):1242-7.
  20. Ojea A, Nogueira JL, Solsona E et al.. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur Urol 2007 November;52(5):1398-406.
  21. Colombel M, Saint F, Chopin D, Malavaud B, Nicolas L, Rischmann P. 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 September;176(3):935-9.
  22. Lamm DL, Colombel M, Persad R. Clinical practice recommendations for the management of non-muscle invasive bladder cancer. Eur.Urol.Suppl. 7, 651-666. 2008. Ref Type: Abstract
  23. Huguet J, Crego M, Sabate S, Salvador J, Palou J, Villavicencio H. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 2005 July;48(1):53-9.
  24. Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M. 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 2008 January;53(1):146-52.

 

 

 

Written by:
Rianne J.M. Lammers, MD, PhD-student and J. Alfred Witjes, MD, PhD† as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

†Author for correspondence:
Radboud University Nijmegen Medical Centre, Department of Urology
Geert Grooteplein Zuid 10 (659)
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
Tel.: 0031 24 361 37 35
Fax.: 0031 24 354 10 31
E-mail:

 

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