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Non-muscle invasive bladder cancer guidelines

Marko Babjuk
Professor of Urology,
2nd Faculty of Medicine,
Charles University,
Prague, Czech Republic
Thomas B Madden MRCS
Department of Urology,
The Royal Liverpool Hospital,
Liverpool, UK
This is a brief overview of the 2011 update of this EAU guideline. The full document and the pocket version are available on the EAU website(1) and a review has also been published in European Urology.(2) Separate guidelines have been developed for the management of upper urinary tract and muscle invasive disease(3,4) as the approach to these aspects of urothelial cancer is very different to the treatment of non-muscle invasive bladder cancer. 
Epidemiology and risk factors
Bladder cancer is more common in men, with a global age-standardised incidence rate of 10.1 per 100,000 for men and 2.5 per 100,000 for women. Approximately 75–85% of newly diagnosed cancers are not muscle invasive (stage Ta, T1 or CIS).
Bladder cancer was first linked to the aromatic amines used in industries such as printing and metal processing. Smoking also plays a significant role in the aetiology: it triples the risk of developing bladder cancer and also leads to a higher mortality on long-term follow-up.
Bladder cancer is classified using the TNM staging system approved by the Union Internationale Contre le Cancer (see Figure 1). An individual cancer is further graded 1–3 depending on its degree of differentiation according to the 1973 World Health Organization grading system, where grade 3 represents a more aggressive cancer. However, this was revised in 2004 in favour of a more descriptive system depending on whether the lesion is flat or papillary. Studies attempting to demonstrate the improved prognostic value of the new system have been controversial and therefore both systems can be used until further evidence has been published.
Carcinoma in situ (CIS) is a flat, high-grade, non-invasive urothelial carcinoma. It is a misnomer as it is a malignant entity itself as well as a precursor of muscle invasive disease.
Owing to significant reporting variability among pathologists it is recommended that biopsy slides are reviewed, especially where a lesion may be T1, CIS or is high grade.
The most common presentations of bladder cancer are with either macroscopic or microscopic haematuria. Rarely patients may present with lower urinary tract symptoms (LUTS). Where bladder cancer is suspected it is recommended that all patients undergo a cystoscopic examination of the bladder, usually performed with a flexible instrument with the patient awake.
Some form of upper tract imaging must also be performed in the initial assessment to diagnose upper tract cancer or other causes of haematuria, such as renal carcinomas. Transabdominal ultrasound is commonly used in the initial assessment although it cannot exclude upper tract urothelial tumours. For such tumours, an intravenous urogram (IVU) or a CT urogram is diagnostic, with CT providing more accurate staging information. However, due to the low incidence of upper urinary tract tumours (1.8%), this form of imaging should be reserved for selected cases, for instance where tumours are located in the trigone where the incidence of upper tract tumours rises to 7.5%.
Urine cytology has a higher sensitivity in the presence of high-grade malignancy or CIS and is recommended to predict the presence of high-grade cancer prior to resection. A number of new urinary biomarkers are being developed to give a higher sensitivity and specificity for the detection of bladder cancer. However, at the time of the last update of the EAU guidelines on non-muscle invasive bladder cancer none of these can be recommended.
Predicting recurrence and progression
The European Organisation for Research and Treatment of Cancer (EORTC) has devised a scoring system and risk tables that can be used to divide patients into low-, intermediate- or high-risk groups for recurrence and progression of their cancer. The tables do not include patients diagnosed with CIS alone (see Tables 1 
and 2). 
Surgical resection
The surgical resection of the bladder tumour is performed as part of the treatment of bladder cancer but it is also necessary to provide a histological diagnosis. It is important to include part of the muscle layer in the resection specimen so that the histopathologist can assess for muscle invasion (stage T2), because this radically changes the prognosis and treatment options. 
Most bladder tumours will present as a papillary lesion attached to the bladder wall on a pedicle, but more malignant lesions can present as an irregular, solid mass, often with necrotic areas. Carcinoma in situ is often more subtle and can present as a velvet-like raised reddish area that is often difficult to distinguish from inflammation. If such a lesion is seen, biopsies must be taken of the area. 
Random biopsies of normal-looking bladder mucosa are recommended when a patient has a tumour with a non-papillary appearance or has positive urine cytology but no visible lesion in the bladder.
A biopsy of the prostatic urethra should be taken in the following circumstances: when a bladder neck tumour is found; when abnormalities of the area are seen; when CIS may be present in the bladder; or when the patient has positive urine cytology without visible abnormalities.
Photodynamic diagnosis, also referred to as fluorescence cystoscopy, is a technique that is gaining widespread support. It involves cystoscopy under blue or violet light following the introduction of a photosensitiser into the bladder. Under these conditions, abnormal areas of mucosa will be revealed that may have appeared normal with standard white light cystoscopy. The technique is especially useful for revealing areas of CIS and should be restricted to patients with positive cytology or a previous high-grade tumour where CIS may be suspected.
There is a considerable risk of residual tumour after the initial resection and 4–25% of T1 tumours are understaged at initial resection. Therefore, a second resection should be considered if: the first resection was incomplete – for instance with large or multiple tumours
  • no muscle tissue was included in the original specimen
  • high-grade or stage T1 tumour was diagnosed 
Adjuvant treatment
Adjuvant chemotherapy for non-muscle invasive bladder cancer is given as an intravesical instillation. There are two main types: intravesical chemotherapy (mitomycin C is most often used); or immunotherapy with live attenuated mycobacterium (bacillus Calmette-Guérin; BCG). The immunotherapy is given to provoke an immune reaction that will attack the malignant cells.
There is a high risk of tumour recurrence following resection. Therefore, a single postoperative dose of chemotherapy should be given on the same day as transurethral resection (TUR). A meta-analysis has shown a reduction in the rate of recurrence from 48.4% to 36.7% with this strategy. Chemotherapy is contraindicated where a perforation of the bladder is suspected. 
The need for further adjuvant therapy depends on the patient’s risk of tumour recurrence or progression (see Table 3).  Immunotherapy with BCG has been proven to be more effective although there is a higher risk of side effects, which is why immunotherapy is reserved for patients at higher risk of progression or cases where chemotherapy has not worked.  When BCG is given, it is advisable for patients to receive maintenance courses for up to a year since it has been shown that there can be an increased risk of recurrence if only a single induction course is given. There is currently no consensus on the optimal frequency or duration of induction and maintenance courses. 
Treatment of CIS
Without any treatment, approximately 54% of patients with CIS will progress to muscle invasive disease. CIS cannot be treated by endoscopic resection alone. Therefore, once the presence of CIS has been established the patient must undergo further treatment to prevent progression to muscle invasive disease. The options are either BCG immunotherapy with maintenance courses for at least one year or cystectomy. With worsening disease or high-grade tumour persisting at 3 and 6 months after starting BCG, cystectomy is recommended. Approximately 10–20% of BCG responders will eventually progress to muscle invasive disease compared with 66% of non-responders. 
Cystectomy for non-muscle invasive disease
Cystectomy is a possible treatment for patients with tumours that have a high risk of progression as defined by the EORT risk tables. The following fall into this category:
  • multiple recurrent high-grade tumours
  • high-grade T1 tumours
  • high-grade tumours with concurrent CIS
The alternative is to offer BCG instillations. It is therefore recommended that both treatment options are discussed with these patients. 
Cystectomy is also indicated when patients have disease recurrence despite BCG therapy.
After resection all patients should have a three-month follow-up with a cystoscopy to check for recurrence. If this is negative, the follow-up for patients with Ta or T1 tumours can be adapted depending on the risk of recurrence. Patients at low risk of recurrence and progression can have a further cystoscopy at nine months and then yearly. Patients at high risk, or who have CIS, should have cystoscopy three-monthly for two years, then six-monthly up to five years and then yearly. These patients should also undergo yearly upper tract imaging.
Where tumour recurrence is detected in patients in the low-risk group (single focus G1 pTa disease), the recurrence is nearly always of low stage and grade. If the lesions are small in these patients, they can be safely destroyed by fulguration without requiring a repeat biopsy.
  1. European Association of Urology. (accessed 20 February 2012)
  2. Marko B et al. EAU Guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 Update. Eur Urol 2011;59:997–1008. 
  3. Rouprêt M et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 Update. Eur Urol 2011;59:584–94. (accessed 20 February 2012).
  4. Stenzl A et al. Bladder cancer muscle-invasive and metastatic. EAU Guidelines. Edition presented at the 26th EAU Annual Congress; 2011; Vienna, Austria. (accessed 20 February 2012).