Beyond the Abstract - A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group, by Maurizio Brausi

BERKELEY, CA (UroToday.com) - Bacillus Calmette-Guérin (BCG) is currently regarded as the most effective intravesical treatment available for the management of non-muscle invasive bladder cancer (NMIBC).

Numerous randomized trials and meta-analyses have confirmed the unparalleled superiority of maintenance BCG in reducing recurrence, progression, and mortality in patients with NMIBC. An international committee of experts in bladder cancer management, known as the International Bladder Cancer Group, reviewed current clinical practice guidelines from the European Association of Urology, American Urological Association, National Comprehensive Cancer Network and the First International Consultation on Bladder Tumors and, based on this review, concluded that BCG induction plus maintenance is the intravesical therapy of choice for high-risk disease, and the preferred option for patients with intermediate-risk disease (see Table 1 for the IBCG’s complete recommendations for the management of NMIBC). Recently, Cochrane investigators systematically reviewed over 80 randomized trials and 11 meta-analyses and concluded that maintenance BCG should be considered the “gold-standard” treatment regimen for patients with intermediate- and high-risk NMIBC, and that chemotherapy be regarded as an option for those failing or who are unsuitable for BCG therapy [Shelley et al. Cancer Treat Rev 2010;26:195-205]. 


 Table 1. IBCG Recommendations for the Management of NMIBC

Risk Category

Definition

Management

Low

Solitary, primary low-grade Ta

     ► Complete TURBT plus immediate, single, post-operative chemotherapeutic instillation*

 

Intermediate

Multiple or recurrent low-grade tumours

     ► BCG induction plus at least 1 year of maintenance or intravesical chemotherapy following a complete TURBT

     ► Adjuvant chemotherapy should not exceed 12 months

 

High

Any T1 and/or G3 and/or CIS

     ► BCG induction plus maintenance following a complete TURBT

     ► Consider immediate radical cystectomy for:

      — high-grade, multiple T1 tumours;

      — T1 tumours located at a site difficult to resect;

      — residual T1 tumours upon re-resection; or,

      — high-grade tumours with CIS 


*Except in those with obvious or suspected bladder wall perforation
TURBT: transurethral resection of the bladder tumour; CIS: carcinoma in situ; BCG: bacillus Calmette-Guérin 


Despite the high level of evidence and guideline recommendations in support of maintenance BCG, experts still argue whether the routine use of maintenance is justified, particularly in intermediate-risk patients, and whether previous intravesical chemotherapy could bias outcomes in favour of BCG. However, recent data from the landmark European Organization for Research and Treatment of Cancer (EORTC) 30911 trial and an individual patient data meta-analysis by Malmström et al.have unequivocally shown BCG to be superior to intravesical chemotherapy in patients with both intermediate- and high-risk NMIBC, and have confirmed that maintenance BCG is more effective than chemotherapy in both patients previously treated and those not previously treated with chemotherapy [Sylvester <em >et al.Eur Urol 2010;57:766-73; Malmström et al. Eur Urol 2009;56:247-56].

Furthermore, the Surveillance, Epidemiology, and End Results (SEER) study, which examined data from patients with NMIBC treated in American academic institutions, also found that BCG therapy is significantly underutilized and that patients with high-risk NMIBC are severely undertreated [Huang et al. J Urol 2008;180:520-4; Chamie et al. Cancer 2011;117:5392-5401]. Common reasons for the underuse of BCG are physician and patient misconceptions and concerns surrounding BCG-associated adverse events. In the past, poor technique and non-recognition of a BCG-related systemic adverse events led to some cases of serious morbidity and, in rare instances, mortality. However, with increasing experience in the use of BCG, side effects now appear to be less prominent, and few if any deaths due to BCG therapy have been reported in the recent literature. In fact, serious side effects are encountered in less than 5% of treated patients, and most adverse events can be successfully managed and even prevented in the majority of cases [Witjes et al. Eur Urol Suppl 2008;7:6767-74].

Educating healthcare professionals on correct catheterization techniques and the use of overall good clinical practice with regard to BCG administration will help prevent BCG-associated adverse events. BCG should not be instilled for at least 2 weeks following a TURBT to minimize the risk of systemic absorption, and should not be instilled in patients exhibiting gross hematuria due to traumatic catheterization, ongoing healing of the epithelium, or infection. BCG should also be instilled passively by gravity. Finally, early recognition of a BCG systemic reaction and initiation of anti-tubercular and quinolone antibiotics may help eliminate most serious adverse events. Evidence also suggests that prophylaxis with ofloxacin may help reduce BCG-associated side effects and improve tolerance to therapy [Colombel et al. J Urol 2006;176:935-9]. (see Table 2 for IBCG-recommended strategies for the prevention of BCG-associated adverse events.) 


 Table 2. IBCG Recommendations for the Prevention of BCG-Associated Adverse Events

 

  • Instill BCG a minimum of 2 weeks after a TURBT
  • Teach proper catheterization techniques to administering healthcare professionals
  • Defer BCG instillations for 1 week if catheterization is traumatic
  • If gross hematuria is present, delay BCG until this has resolved
  • If the patient has a UTI, then defer BCG for 1 week until resolution of the UTI with antibiotics and culture is negative
  • Consider the use of ofloxacin 200 mg given twice after each BCG instillation
  • If a BCG systemic reaction is suspected, then early initiation of multiple antimicrobial therapies and consultation with an infectious diseases specialist (if available) are recommended 
  • Consider dose reductions in patients known to be intolerant to standard-dose BCG

 TURBT: transurethral resection of the bladder tumour; UTI: urinary tract infection BCG: bacillus Calmette-Guérin 


In summary, level 1 evidence has concluded that maintenance BCG is superior to both chemotherapy and induction BCG alone for the prevention of recurrence and progression of NMIBC. Therefore, maintenance BCG should be considered the gold-standard therapy for the prophylaxis and management of NMIBC.

 

Written by:
Maurizio Brausi, MD 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.

A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group - Abstract

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