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European Urology
Volume 54, issue 2, pages 241-482, August 2008Reviews
EAU Guidelines on Non-Muscle-Invasive Urothelial Carcinoma of the Bladder 00526-5/assets/eulogo1.jpg)
Marko Babjuk a 
, Willem Oosterlinck b, Richard Sylvester c, Eero Kaasinen d, Andreas Böhle e, Juan Palou-Redorta f.
Accepted 22 April 2008, Published online 30 April 2008, pages 303 - 314
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Abstract
Context and objective
To present the updated version of 2008 European Association of Urology (EAU) guidelines on non-muscle-invasive bladder cancer.
Evidence acquisition
A systematic review of the recent literature on the diagnosis and treatment of non-muscle-invasive bladder cancer was performed. The guidelines were updated and the level of evidence and grade of recommendation were assigned.
Evidence synthesis
The diagnosis of bladder cancer depends on cystoscopy and histologic evaluation of the resected tissue. A complete and correct transurethral resection (TUR) is essential for the prognosis of the patient. When the initial resection is incomplete or when a high-grade or T1 tumour is detected, a second TUR within 2–6 wk should be performed.
The short- and long-term risks of both recurrence and progression may be estimated for individual patients using the scoring system and risk tables. The stratification of patients to low, intermediate, and high-risk groups—separately for recurrence and progression—represents the cornerstone for indication of adjuvant treatment. In patients at low risk of tumour recurrence and progression, one immediate instillation of chemotherapy is strongly recommended. In those at an intermediate or high risk of recurrence and an intermediate risk of progression, one immediate instillation of chemotherapy should be followed by further instillations of chemotherapy or a minimum of 1 yr of bacillus Calmette-Guerin (BCG). In patients at high risk of tumour progression, after an immediate instillation of chemotherapy, intravesical BCG for at least 1 yr is indicated. Immediate cystectomy may be offered to the highest risk patients and in patients with BCG failure. The long version of the guidelines is available on www.uroweb.org.
Conclusions
These EAU guidelines present the updated information about the diagnosis and treatment of non-muscle-invasive bladder cancer and offer the recent findings for the routine clinical application.
Keywords: Bacillus Calmette-Guerin (BCG), Bladder cancer, Cystectomy, Cystoscopy, Diagnosis, EAU Guidelines, Follow-up, Intravesical chemotherapy, Prognosis, Transurethral resection (TUR).
Article Outline
- Abstract
- Take Home Message
- 1. Background
- 2. Epidemiology
- 3. Classification
- 4. Risk factors
- 5. Diagnosis
- 6. Predicting recurrence and progression
- 7. Adjuvant intravesical chemotherapy
- 8. Adjuvant intravesical BCG immunotherapy
- 9. Treatment of failures of intravesical therapy
- 10. Cystectomy
- 11. Follow-up
- References
- Copyright
1. Background
The first European Association of Urology (EAU) guidelines on bladder cancer were published in 2002 [1]. Since then, the long version of the guidelines has been updated continuously, with the most recent version available on www.uroweb.org. This overview represents an updated version of 2008 EAU guidelines on non-muscle-invasive bladder cancer.
2. Epidemiology
Bladder carcinoma is the most common malignancy of the urinary tact. In Europe, the highest incidence (ASR = age standardized rate) is reported from the western (23.6 in males and 5.4 in females) and southern parts (27.1 in males and 4.1 in females), followed by northern Europe (16.9 in males and 4.9 in females). The lowest incidence can be observed in eastern European countries (14.7 in males and 2.2 in females, respectively) [2].
Approximately 75–85% of patients with bladder cancer present with the disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1).
3. Classification
The 2002 tumour, node, metastatis (TNM) classification approved by the Union International Contre le Cancer (UICC) has been widely accepted and is used in these guidelines (Table 1) [3].
Table 1 2002 TNM classification of urinary bladder cancer
| T – Primary tumour | ||
| TX | Primary tumour cannot be assessed | |
| T0 | No evidence of primary tumour | |
| Ta | Non-invasive papillary carcinoma | |
| Tis | Carcinoma in situ: ‘flat tumour’ | |
| T1 | Tumour invades subepithelial connective tissue | |
| T2 | Tumour invades muscle | |
| T2a | Tumour invades superficial muscle (inner half) | |
| T2b | Tumour invades deep muscle (outer half) | |
| T3 | Tumour invades perivesical tissue: | |
| T3a | Microscopically | |
| T3b | Macroscopically (extravesical mass) | |
| T4 | Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall | |
| T4a | Tumour invades prostate, uterus, or vagina | |
| T4b | Tumour invades pelvic wall or abdominal wall | |
| N – Lymph nodes | ||
| NX | Regional lymph nodes cannot be assessed | |
| N0 | No regional lymph node metastasis | |
| N1 | Metastasis in a single lymph node 2 cm or less in greatest dimension | |
| N2 | Metastasis in a single lymph node more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, none more than 5 cm in greatest dimension | |
| N3 | Metastasis in a lymph node more than 5 cm in greatest dimension | |
| M – Distant metastasis | ||
| MX | Distant metastasis cannot be assessed | |
| M0 | No distant metastasis | |
| M1 | Distant metastasis | |
The new classification for grading of non-invasive urothelial tumours was proposed by the World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) and published by the WHO in 2004 (Table 2) [4]. It differentiates between papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade and high-grade urothelial carcinomas.
Table 2 WHO grading in 1973 and in 2004
| 1973 WHO grading | |
| Urothelial papilloma | |
| Grade 1: | well differentiated |
| Grade 2 | moderately differentiated |
| Grade 3: | poorly differentiated |
| 2004 WHO grading | |
| Urothelial papilloma | |
| Papillary urothelial neoplasm of low malignant potential (PUNLMP) | |
| Low-grade papillary urothelial carcinoma | |
| High-grade papillary urothelial carcinoma | |
WHO = World Health Organization.
The PUNLMP are lesions that do not have cytological features of malignancy but show normal urothelial cells in a papillary configuration. They have a negligible risk for progression, but still have a tendency to recur. The intermediate grade (grade 2), which was the subject of controversy in the 1973 WHO classification, has been eliminated.
Until the 2004 WHO classification has been validated by more clinical trials, tumours should be graded using both the 1973 and the 2004 WHO classifications (Table 2).
Despite well-defined criteria, there is important interobserver variability in classifying dysplasia and carcinoma in situ (CIS, Tis), stage T1 versus Ta tumours and grading of the tumours [5]. As a consequence, we recommend that the urologist reviews histologic findings with the pathologist.
4. Risk factors
The urologist should be aware of the types of occupational exposures that may be related to urothelial carcinogens [6]. Aromatic amines were the first to be recognized. At-risk groups include workers in the following industries: printing, iron, and aluminium processing, industrial painting, gas and tar manufacturing (level of evidence: 3).
Another prominent risk factor is cigarette smoking, which triples the risk of developing bladder cancer and leads to its higher mortality [7] (level of evidence: 3).
5. Diagnosis
Haematuria is the most common finding in non-muscle-invasive bladder tumours. Bladder irritation, dysuria, or urgency may be symptoms of CIS.
5.1. Imaging
Using intravenous urography (IVU) large tumours may be seen as filling defects in the bladder. It is also utilized to detect filling defects in the upper urinary tract or hydronephrosis, which may indicate the presence of a ureteral tumour. The necessity to perform routine IVU is now questioned because of the low incidence of significant findings [8], and [9] (level of evidence: 3). The incidence of simultaneous upper urinary tract tumours is low (1.8%), but increases to 7.5% in tumours located in the trigone [8]. The risk of tumour recurrence in the upper urinary tract during follow-up increases in multiple and high-risk tumours [9].
In many centres, CT urography is used as an alternative to conventional IVU.
Transabdominal ultrasound (US) permits characterization of renal masses, detection of hydronephrosis, and visualization of intraluminal filling defects in the bladder. Combined with plain abdominal film, it can be as accurate as IVU in the diagnosis of the cause of haematuria (level of evidence: 3).
5.2. Urinary cytology
Examination of a voided urine or bladder washing specimen for exfoliated cancer cells has high sensitivity in high-grade tumours but low sensitivity in low-grade tumours (level of evidence: 2a) [10]. It is thus useful when a high-grade malignancy or CIS is present; however, a negative result cannot exclude the presence of a low-grade cancer.
Positive urinary cytology may indicate urothelial tumour anywhere in the urinary tract. Cytological interpretation is user dependent [11]. The evaluation can be hampered by low cellular yield, urinary tract infections, stones, or intravesical instillations. In experienced hands however the specificity exceeds 90% [10] (level of evidence: 2a). Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable, as cytolysis may be often present.
5.3. Urine molecular tests
Several tests based on detection of soluble or cell-associated markers in urine are available [10]. Most of these tests have a better sensitivity for detecting bladder cancer than urinary cytology, but specificity is lower (level of evidence: 2a). It remains unclear whether these tests offer additional information which is useful for detection and management of non-muscle-invasive bladder tumours [10]. Moreover, the additional costs of some of these tests should be considered.
5.4. Cystoscopy
The diagnosis of bladder cancer ultimately depends on cystoscopic examination and histologic evaluation of the resected tissue.
In general, cystoscopy is initially performed in the office, using flexible instruments. If a bladder tumour has been visualized in earlier imaging studies, a diagnostic cystoscopy can be omitted.
A careful description of the finding is necessary. It should include the site, size, number, and appearance (papillary or solid) of the tumours as well as a description of mucosal abnormalities.
5.5. Transurethral resection (TUR)
The goal of the TUR in TaT1 bladder tumours is to make the correct diagnosis and remove all visible lesions.
Small tumours (less than 1 cm) can be resected en bloc, the specimen should contain a part of the underlying bladder wall. Some experts believe that a deep resection is not necessary in small, apparently low-grade lesions with a previous history of TaG1 tumour.
Larger tumours should be resected separately in fractions, which include the exophytic part of the tumour, the underlying bladder wall with the detrusor muscle, and the edges of the resection area. The specimens from different fractions must be referred to the pathologist in separate containers. Cauterization has to be avoided as much as possible during the resection to prevent tissue destruction.
The pathologic report should specify the grade of the lesion, and the depth of tumour invasion into the bladder wall and give information on whether the lamina propria and muscle are present in the specimen [12].
A complete and correct TUR is essential for the prognosis of the patient [13].
5.6. Bladder and prostatic urethra biopsies
Bladder tumours are often multifocal. Moreover, TaT1 tumours can be accompanied by CIS or dysplasia. These lesions may present themselves as velvet-like, reddish areas indistinguishable from inflammation or may be not visible at all.
The biopsies from normal-looking mucosa in patients with TaT1 tumours, so-called random biopsies (R-biopsies) or selected site mucosal biopsies, are not routinely recommended. The likelihood of detecting CIS in low-risk tumours is extremely low (less than 2%), and the choice of adjuvant intravesical therapy is not influenced by the biopsy result [14] (level of evidence: 2a). Cold cup biopsies from normal-looking mucosa should be performed when cytology is positive or when exophytic tumour is of nonpapillary appearance. When abnormal areas of urothelium are seen, it is advised to take “cold cup” biopsies or biopsies with a resection loop. Material obtained by random or directed biopsies must be sent for pathologic assessment in separate containers.
The involvement of the prostatic urethra and ducts in male patients with TaT1 bladder tumours has been reported. Although the exact risk is not known, it seems to be higher if the tumour is located on the trigone or bladder neck, in the presence of bladder CIS, and in multiple tumours [15], and [16] (level of evidence: 3). In these cases and when cytology is positive with no evidence of tumour in the bladder or when abnormalities of prostatic urethra are visible, biopsies of the prostatic urethra should be considered.
5.7. Fluorescence cystoscopy
The use of white light may lead to missing lesions that are present but not visible.
Fluorescence cystoscopy is performed using violet light after intravesical instillation of a photosensitizer or its precursor, usually 5-aminolevulinic acid (5-ALA) or hexylaminolevulinate (HAL). It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures in detecting malignant tumour, particularly CIS [17] (level of evidence: 2a). False positivity, however, can be induced by inflammation and recent TUR or intravesical instillation.
The benefit of fluorescence-guided TUR for recurrence-free survival was shown in several small randomised clinical trials [18], but its definitive value in improving the outcome of patients for progression rates or survival remains to be proven. The additional costs of the equipment should be considered.
5.8. Second resection
The significant risk of residual tumour after the initial TUR of TaT1 lesions has been demonstrated [13], and [19] (level of evidence:1). Moreover, the tumour may be understaged by the initial resection.
A second TUR should be considered if there is a suspicion that the initial resection was incomplete, eg when multiple or large tumours are present or when the pathologist reported no muscle tissue in the specimen. Furthermore, it should be performed when a high-grade non-muscle-invasive tumour or a T1 tumour was detected at the initial TUR.
It has been demonstrated that a second TUR can increase recurrence-free and progression-free survival [20] (level of evidence: 2a). Most authors recommend resection 2–6 wk after the initial TUR. The procedure should include a resection of the primary tumour site. The summary of recommendations for diagnosis of non-muscle-invasive bladder cancer is presented in Table 3.
Table 3 Recommendations for diagnosis of non-muscle-invasive bladder tumours
| • Renal and bladder ultrasonography, intravenous urography (IVU) or CT-urography in selected cases (tumours located in the trigone) (grade of recommendation: B). |
| • Cystoscopy with description of the tumour (site, size, number, and appearance) and mucosal abnormalities. |
| • Urine cytology. |
| • Transurethral resection (TUR) in one piece for small tumours (less than 1 cm). The specimen should contain a part of the underlying bladder wall (grade of recommendation: B). |
| • TUR in fractions (including muscle tissue) for larger tumours (grade of recommendation: B). |
| • Biopsies of abnormal-looking urothelium, biopsies from normal-looking mucosa when cytology is positive or when exophytic tumour is of nonpapillary appearance (grade of recommendation: C). |
| • Biopsy of the prostatic urethra in the case of bladder neck tumour, when bladder CIS is present or suspected, in the case of positive cytology without evidence of tumour in the bladder or when abnormalities of prostatic urethra are visible. If it was not performed during the initial procedure it can be completed at the time of the second resection. The biopsy is taken using resection loop from the precolicular area (grade of recommendation: C). |
| • If equipment is available, fluorescence-guided biopsy when bladder CIS is suspected (eg positive cytology, recurrent tumour with previous history of a high grade lesion) (grade of recommendation: C). |
| • A second TUR 2–6 wk after the initial resection when it was incomplete or when a high-grade or T1 tumour was detected (grade of recommendation: B). |
| • The pathological report should specify the grade, the depth of tumour invasion, and whether the lamina propria and muscle are present in the specimen (grade of recommendation: C). |
6. Predicting recurrence and progression
The classic way to categorize patients with TaT1 tumours is to divide them into risk groups based on prognostic factors derived from multivariate analyses. In order to separately predict the short-term and long-term risks of both recurrence and progression in individual patients, a scoring system and risk tables have been developed [21]. The basis was the European Organization for Research and Treatment of Cancer (EORTC) database, which provided individual patient data for 2596 patients diagnosed with TaT1 tumours randomized in seven trials, which did not contain a second TUR and maintenance bacillus Calmette-Guerin (BCG) therapy. The scoring system is based on the six most significant clinical and pathological factors:
•Number of tumours
•Tumour size
•Prior recurrence rate
•T category
•Presence of concomitant CIS
•Tumour grade.
Table 4 illustrates the weights applied to various factors for calculating the total scores for recurrence and progression. Table 5 shows the total scores stratified, as in the original article [21], into four categories reflecting various probabilities of recurrence and progression at 1 and 5 yr. With combining two of the four categories distinctly in recurrence and progression, the EAU working group suggests to use, as shown in the rightmost column in Table 5, a 3-tier system defining low, intermediate, and high-risk groups for recurrence and progression.
Table 4 Weighting used to calculate recurrence and progression scores (CIS = carcinoma in situ)
| Factor | Recurrence | Progression |
|---|---|---|
| Number of tumours | ||
| Single | 0 | 0 |
| 2 to 7 | 3 | 3 |
| ≥8 | 6 | 3 |
| Tumour diameter | ||
| <3 cm | 0 | 0 |
| ≥3 cm | 3 | 3 |
| Prior recurrence rate | ||
| Primary | 0 | 0 |
| ≤1 recurrence/yr | 2 | 2 |
| >1 recurrence/yr | 4 | 2 |
| Category | ||
| Ta | 0 | 0 |
| T1 | 1 | 4 |
| Concomitant CIS | ||
| No | 0 | 0 |
| Yes | 1 | 6 |
| Grade (1973 WHO) | ||
| G1 | 0 | 0 |
| G2 | 1 | 0 |
| G3 | 2 | 5 |
| Total score | 0–17 | 0–23 |
Table 5 Probability of recurrence and progression according to total score (electronic calculators for Tables 4 and 5 are available at http://www.eortc.be/tools/bladdercalculator/)
| Recurrence score | Probability of recurrence at 1 yr | Probability of recurrence at 5 yr | Recurrence risk group | ||
|---|---|---|---|---|---|
| % | (95% CI) | % | (95% CI) | ||
| 0 | 15 | (10–19) | 31 | (24–37) | Low risk |
| 1–4 | 24 | (21–26) | 46 | (42–49) | Intermediate risk |
| 5–9 | 38 | (35–41) | 62 | (58–65) | Intermediate risk |
| 10–17 | 61 | (55–67) | 78 | (73–84) | High risk |
| Progression score | Probability of progression at 1 yr | Probability of progression at 5 yr | Progression risk group | ||
|---|---|---|---|---|---|
| % | (95% CI) | % | (95% CI) | ||
| 0 | 0.2 | (0–0.7) | 0.8 | (0–1.7) | Low risk |
| 2–6 | 1 | (0.4–1.6) | 6 | (5–8) | Intermediate risk |
| 7–13 | 5 | (4–7) | 17 | (14–20) | High risk |
| 14–23 | 17 | (10–24) | 45 | (35–55) | High risk |
7. Adjuvant intravesical chemotherapy
7.1. One, immediate, post-operative intravesical instillation
TaT1 tumours recur frequently and progress to muscle-invasive disease in a limited number of cases. It is therefore necessary to consider adjuvant therapy in all patients.
In meta-analysis of seven randomized trials, one immediate instillation of chemotherapy after TUR decreased the percent of patients with recurrence by 12% and the odds of recurrence by 39%. The benefit was confirmed in single and multiple tumours [22] (level of evidence: 1a).
The difference of 12% means that 8.5 patients must be treated to prevent one recurrence.
The effect can be explained by the destruction of circulating tumour cells or as an ablative effect of residual tumour cells at the resection site.
The timing of the instillation is crucial. In all studies, the instillation was administered within 24 h. One study reported that if the first instillation was not given the same day as TUR, there was a twofold increase in the relative risk of recurrence [23] (level of evidence: 2a).
Mitomycin C (MMC), epirubicin, and doxorubicin have all shown a comparable beneficial effect [22] (level of evidence: 1b).
Severe complications are very rare. They have been reported when extravasation of the drug occurred [24]. Thus, an immediate instillation should be omitted in case of overt or suspected intra- or extraperitoneal perforation, which is most likely to appear in extensive TUR procedures. Clear instructions should be given to the nursing staff for controlling the free flow of the bladder catheter at the end of the instillation.
7.2. Additional intravesical chemotherapy instillations
The need for further adjuvant intravesical therapy depends on the patient's prognosis. In patients with a low risk of recurrence (Table 5), a single immediate instillation may be considered to be sufficient treatment [22] (level of evidence: 1a). For other patients, however, it remains an incomplete treatment as the likelihood of recurrence and/or progression is considerable.
The effect of the immediate instillation of chemotherapy occurs during the first and second year [25] (level of evidence: 1b).
The choice between further chemotherapy or BCG immunotherapy largely depends on the risk that needs to be reduced: recurrence or progression. A meta-analysis comparing intravesical chemotherapy to TUR alone demonstrated that chemotherapy prevents recurrence but not progression [26] (level of evidence: 1a). The efficacy of intravesical chemotherapy in reducing the risk of tumour recurrence was confirmed by two other meta-analyses in primary [27] and recurrent tumours [28].
It is still controversial how long and how frequently intravesical chemotherapy instillations have to be given. From a systematic review of the literature of randomised clinical trials, comparing different schedules of intravesical chemotherapy instillations, one could only conclude that the ideal duration and intensity of the schedule remains undefined because of conflicting data [29].
7.3. Optimizing intravesical chemotherapy
It was demonstrated that adapting the urinary pH, decreasing the urinary excretion, and buffering the intravesical solution reduce the recurrence rate [30] (level of evidence: 1b).
Concentration was more important than the duration of the treatment [31] (level of evidence: 1b). In view of these data, it seems advisable to dissolve the drug in a buffered solution at optimal pH and to ask the patient not to drink the morning before instillation.
8. Adjuvant intravesical BCG immunotherapy
Four meta-analyses confirmed that BCG after TUR is superior to TUR alone or TUR and chemotherapy in preventing recurrences of TaT1 tumours [32], [33], [34], and [35] (Level of evidence: 1a).
Two meta-analyses demonstrated that BCG therapy prevents, or at least delays, the risk of tumour progression [36], and [37] (level of evidence: 1a). A reduction of 27% in the odds of progression with BCG treatment was noted (p = 0.0001). The size of the reduction is similar in patients with TaT1 tumours and in those with CIS [36].
Another two meta-analyses, however, suggested a possible bias in favour of BCG by the inclusion of patients previously treated with intravesical chemotherapy [38], and [39].
8.1. The optimal BCG schedule and dose
For optimal efficacy, the BCG must be given in a maintenance schedule [35], [36], and [37] (level of evidence: 1a). In the EORTC meta-analysis, only patients receiving maintenance BCG benefited. In the four trials where no maintenance was given, no reduction in progression was observed. In the 20 trials in which some form of BCG maintenance was given, a reduction of 37% in the odds of progression was observed (p = 0.00004). The meta-analysis was unable to determine which BCG maintenance schedule was the most effective [36]. In a meta-analysis, it was concluded that at least 1 yr of maintenance BCG was required to show the superiority of BCG over MMC in preventing recurrence or progression [35], and [37].
Induction BCG instillations are classically given according to the empirical 6-wk induction schedule, and many different maintenance schedules have been used with up to 30 instillations given over 3 yr [40]. The optimal number of induction instillations and the optimal frequency and duration of maintenance instillations remain unknown. Based on the extent of intravesical immune response, it is suggested that 3 consecutive weekly instillations give a maximum response [41].
To reduce toxicity, one-third and one-quarter dose of BCG were proposed. Comparing one-third dose to full-dose no overall difference in efficacy was found. However, there was a suggestion that a full dose of BCG may be more effective in multifocal disease [42] (level of evidence: 1b). Although fewer patients reported toxicity with the reduced dose, the incidence of severe systemic toxicity was similar. Further reduction to one-sixth dose was followed by a decrease of efficacy with equal toxicity [43].
8.2. BCG toxicity
Deaths due to BCG sepsis and the high frequency of BCG-induced cystitis have compromised the use of BCG. However, with increased experience in applying BCG, the side-effects now appear to be less prominent. Serious side-effects are encountered in fewer than 5% of patients [44] (level of evidence: 1b). Major complications can appear after systemic absorption of the drug. BCG thus should not be administered during the first 2 wk after TUR, in patients with haematuria and after traumatic catheterization.
8.3. Indications for BCG
Although BCG is a very effective treatment, consensus exists that not all patients with non-muscle-invasive bladder cancer should be treated with BCG due to the risk of toxicity. BCG may be considered to be overtreatment for tumours at low risk of recurrence and progression (Table 5). In patients with tumours at high risk of progression, after an immediate instillation of chemotherapy, BCG including a maintenance schedule is indicated.
Although patients at intermediate risk of progression were included in the meta-analyses [35], and [37], a separate confirmation of the superiority of BCG in these patients is not available. BCG can be offered in this group if chemotherapy is badly tolerated or if the patient continues to recur in spite of repeated chemotherapy instillations. BCG should than be given for at least 1 yr. Recommendations for intravesical therapy are summarized in Table 6.
Table 6 Recommendations for adjuvant therapy
| • The type of intravesical therapy is based on the risk groups as designed in Table 5. |
| • In patients at low risk of tumour recurrence and progression, one immediate instillation of chemotherapy is strongly recommended as the complete adjuvant treatment (grade of recommendation: A). |
| • In patients at an intermediate or high risk of recurrence and an intermediate risk of progression, one immediate instillation of chemotherapy should be followed by further instillations of chemotherapy or a minimum of 1 yr of bacillus Calmette-Guerin (grade of recommendation: A). |
| • If chemotherapy is given, it is advised to use the drug at its optimal pH and to maintain the concentration of the drug during instillation by reducing fluid intake. The optimal schedule and the duration of the chemotherapy instillations remain unclear, but it should probably be given for 6–12 mo (grade of recommendation: B). |
| • In patients at high risk of tumour progression, after an immediate instillation of chemotherapy, intravesical BCG for at least 1 yr is indicated (grade of recommendation: A). |
| • Immediate cystectomy may be offered to patients at highest risk of tumour progression. In patients with BCG failure, cystectomy is recommended (grade of recommendation: C). |
9. Treatment of failures of intravesical therapy
Patients with non-muscle-invasive recurrences after intravesical chemotherapy can profit from BCG instillations [38].
Treatment with BCG is considered to have failed in following situations:
•If muscle-invasive tumour is detected.
•If high-grade non-muscle-invasive tumour is present at both 3 and 6 mo [45]. In patients with tumour presence at 3 mo an additional BCG course provokes complete response in more than 50% of cases [45], and [46].
•Any worsening of the disease under BCG treatment, such as a higher number of recurrences, higher T or grade, appearance of CIS, in spite of initial response (level of evidence: 3).
Patients with a later recurrence after completion of BCG therapy can be treated according to the risk classification (Table 4, and Table 5).
Changing from BCG to intravesical chemotherapy or device-assisted chemotherapy instillations can yield responses in selected cases with BCG failure. Experience however is limited and these strategies are considered experimental. Because of the high risk of development of muscle-invasive tumour in these patients [45], and [47] (level of evidence 3) immediate cystectomy is strongly advocated.
10. Cystectomy
Many experts consider it is reasonable to propose immediate cystectomy to those patients who are at high risk of progression. According to the risk tables of the EORTC (Table 4, and Table 5) these are:
•Multiple recurrent high-grade tumours
•High-grade T1 tumours
•High-grade tumours with concomitant CIS.
Cystectomy is advocated in patients with BCG failure. Delaying cystectomy in these patients may lead to decreased disease specific survival [48].
11. Follow-up
Because of the risk of recurrence and progression, patients need to be followed. However, the frequency and duration of cystoscopies and upper urinary tract investigations should reflect the degree of risk [21]:
•The prompt detection of muscle-invasive and high-grade non-muscle-invasive recurrences is critical, where a delay in diagnosis and therapy threatens a patient's life.
•Tumour recurrence in the low-risk group is nearly always low stage and low grade. Small, non-invasive (Ta), low-grade papillary recurrences do not present an immediate danger to the patient and their early detection is not essential for successful therapy [49] (level of evidence: 2b).
•The result of the first cystoscopy after TUR at 3 mo is a very important prognostic factor for recurrence and for progression [21], [47], and [50] (level of evidence: 1a). The first cystoscopy should thus always be performed 3 mo after TUR.
•The risk of upper urinary tract recurrence increases in patients with multiple and high-risk tumours [9] (level of evidence: 3).
Recommendations for the follow-up schedule are presented in Table 7.
Table 7 Recommendations for follow-up cystoscopy
| • Patients with tumours at low risk of recurrence and progression should have a cystoscopy at 3 mo. If negative, the following cystoscopy is advised at 9 mo and consequently yearly for 5 yr (grade of recommendation: C). |
| • Patients with tumours at high risk of progression should have a cystoscopy and urinary cytology at 3 mo. If negative, the following cystocopies and cytologies should be repeated every 3 mo for a period of 2 yr, every 4 mo in the third year, every 6 mo thereafter until 5 yr, and yearly thereafter. A yearly exploration of the upper tract is recommended (grade of recommendation: C). |
| • Patients with intermediate risk of recurrence and/or progression should have an in-between follow-up scheme using cystoscopy and cytology, adapted according to individual factors (grade of recommendation: C). |
Author contributions: Marko Babjuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Babjuk, Oosterlinck, Sylvester, Kaasinen, Böhle, Palou-Redorta.
Acquisition of data: Babjuk, Oosterlinck, Sylvester, Kaasinen, Böhle, Palou-Redorta. Analysis and interpretation of data: Babjuk, Oosterlinck, Sylvester, Kaasinen, Böhle, Palou-Redorta.
Drafting of the manuscript: Babjuk, Oosterlinck, Sylvester, Kaasinen, Böhle, Palou-Redorta.
Critical revision of the manuscript for important intellectual content: Babjuk, Oosterlinck, Sylvester, Kaasinen, Böhle, Palou-Redorta.
Statistical analysis: Sylvester.
Obtaining funding: none.
Administrative, technical, or material support: none.
Supervision: none.
Other: none.
Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: none.
Funding/Support and role of the sponsor: none.
References
- [1] W. Oosterlinck, B. Lobel, G. Jakse, P.-U. Malmström, M. Stöckle, C. Sternberg, The EAU Working Group on Oncological Urology. Guidelines on bladder cancer. Eur Urol 41 (2002) (105 - 112) Abstract, Full-text, PDF, Crossref.
- [2] Ferlay J, Bray F, Pisani P, Parkin DM. Globcan 2002, Cancer Incidence, Mortality and Prevalence Worldwide, IARC Cancer Base No. 5, version 2.0. Lyon: IARCC Press; 2004.
- [3] D.H. Sobin, Ch. Wittekind. TNM classification of malignant tumours. 6th ed. (Wiley-Liss, New York, USA, 2002) p. 199–202
- [4] G. Sauter, F. Algaba, M. Amin, et al.. Tumours of the urinary system: non-invasive urothelial neoplasias. J.N. Eble, G. Sauter, Epstein Jl, I. Sesterhenn (Eds.) WHO Classification of Tumours of the Urinary System and Male Genital Organs (IARCC Press, Lyon, 2004)
- [5] M. Bol, J. Baak, S. Buhr-Wildhagen, et al.. Reproducibility and prognostic variability of grade and lamina propria invasion in stages Ta, T1 urothelial carcinoma of the bladder. J Urol 169 (2003) (1291 - 1294) Crossref.
- [6] P.J. McCahy, C.A. Harris, E. Neal. The accuracy of recording of occupational history in patients with bladder cancer. Br J Urol 79 (1997) (91 - 93)
- [7] M.P. Zeegers, F.E. Tan, E. Dorant, P.A. van den Brandt. The impact of characteristics of cigarette smoking on urinary tract cancer risk: a meta-analysis of epidemiologic studies. Cancer 89 (2000) (630 - 639) Crossref.
- [8] J. Palou, F. Rodriguez-Rubio, J. Huguet, et al.. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumours. J Urol 174 (2005) (859 - 861) Crossref.
- [9] F. Millan-Rodriguez, G. Chechile-Toniolo, J. Salvador-Bayarri, et al.. Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups. J Urol 164 (2000) (1183 - 1187) Crossref.
- [10] V.B. Lokeshwar, T. Habuchi, H.B. Grossman, et al.. Bladder tumor markers beyond cytology: international consensus panel on bladder tumor markers. Urology 66 (Suppl 6A) (2005) (35 - 63) Crossref.
- [11] M.-P. Raitanen, R. Aine, E. Rintala, et al.. Differences between local and review urinary cytology and diagnosis of bladder cancer. An interobserver multicenter analysis. Eur Urol 41 (2002) (284 - 289) Abstract, Full-text, PDF, Crossref.
- [12] A. Lopez-Beltran, P. Bassi, M. Pavone-Macaluso, R. Montironi. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. Eur Urol 45 (2004) (257 - 266) Abstract, Full-text, PDF, Crossref.
- [13] M. Brausi, L. Collette, K. Kurth, et al., EORTC Genito-Urinary Tract Cancer Collaborative Group. 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 41 (2002) (523 - 531) Abstract, Full-text, PDF, Crossref.
- [14] Van der Meijden A, Oosterlinck W, Brausi M, Kurth KH, Sylvester R, de Balincourt C. Significance of bladder biopsies in Ta,T1 bladder tumours: a report of the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee. Eur Urol 1999; 35:267–71.
- [15] H. Matzkin, M.S. Soloway, S. Hardeman. Transitional cell carcinoma of the prostate. J Urol 146 (1991) (1207 - 1212)
- [16] M.U. Mungan, A.E. Canda, E. Tuzel, K. Yorukoglu, Z. Kirkali. Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder. Eur Urol 48 (2005) (760 - 763) Abstract, Full-text, PDF, Crossref.
- [17] J. Schmidbauer, F. Witjes, N. Schmeller, R. Donat, M. Susani, M. Marberger, Hexvix PCB301/01 Study Group. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 171 (2004) (135 - 138) Crossref.
- [18] S. Denziger, M. Burger, B. Walter. Clinically relevant risk of reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study. Urology 69 (2007) (675 - 679)
- [19] G. Jakse, F. Algaba, P.-U. Malmström, W. Oosterlinck. A second-look TUR in T1 transitional cell carcinoma: why?. Eur Urol 45 (2004) (539 - 546) Abstract, Full-text, PDF, Crossref.
- [20] R.T. Divrik, Ü. Yildirim, F. Zorlu, H. Özen. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumours of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol 175 (2006) (1641 - 1644) Crossref.
- [21] R.J. Sylvester, A.P.M. van der Meijden, W. Oosterlinck, 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 49 (2006) (466 - 477) Abstract, Full-text, PDF, Crossref.
- [22] R. Sylvester, W. Oosterlinck, A. van der Meijden. 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 171 (2004) (2186 - 2190) Crossref.
- [23] E. Kaasinen, E. Rintala, P. Hellström, et al., The FinnBladder Group. Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma. Eur Urol 42 (2002) (167 - 174) Abstract, Full-text, PDF, Crossref.
- [24] J.R. Oddens, A.P.M. van der Meijden, R. Sylvester. One immediate postoperative instillation of chemotherapy in low risk Ta, T1 bladder cancer patients. Is it always safe?. Eur Urol 46 (2004) (336 - 338) Abstract, Full-text, PDF, Crossref.
- [25] E. Solsona, I. Iborra, J.V. Ricos, J.L. Monros, J. Casanova, R. Dumont. Effectiveness of a single immediate mitomycin C instillation in patients with low risk superficial bladder cancer: short and long-term follow-up. J Urol 161 (1999) (1120 - 1123)
- [26] Pawinski A, Sylvester R, Kurth KH, 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. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council Working Part on Superficial Bladder Cancer. J Urol 1996; 156:1934–41.
- [27] M. Huncharek, J.-F. Geschwind, B. Witherspoon, R. McGarry, D. Adcock. Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials. J Clin Epid 53 (2000) (676 - 680) Crossref.
- [28] M. Huncharek, R. McGarry, B. Kupelnick. Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis. Anticancer Res 21 (2001) (765 - 770)
- [29] R.J. Sylvester, W. Oosterlinck, J.A. Witjes. 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 53 (2008) (709 - 719) Abstract, Full-text, PDF, Crossref.
- [30] J.L. Au, R.A. Badalament, M.G. Wientjes, et al.. International Mitomycin C Consortium. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 93 (2001) (597 - 604) Crossref.
- [31] Kuroda M, Niijima T, Kotake T, Akaza H, Hinotsu S. Effect of prophylactic treatment with intravesical epirubicin on recurrence of superficial bladder cancer—The 6th Trial of the Japanese Urological Cancer Research Group (JUCRG): a randomized trial of intravesical epirubicin at dose of 20 mg/40 ml, 30 mg/40 ml, 40 mg/40 ml. Eur Urol 2004; 45:600–5.
- [32] M.D. Shelley, H. Kynaston, J. Court, et al.. A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection versus transurethral resection alone in Ta and T1 bladder cancer. BJU International 88 (2001) (209 - 216) Crossref.
- [33] R.F. Han, J.G. Pan. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 67 (2006) (1216 - 1223) Crossref.
- [34] M.D. Shelley, T.J. Wilt, J. Court, B. Coles, H. Kynaston, M.D. Mason. Intravesical bacillus Calmette-Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU International 93 (2004) (485 - 490) Crossref.
- [35] A. Böhle, D. Jocham, P.R. Bock. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 169 (2003) (90 - 95) Crossref.
- [36] R.J. Sylvester, van der Meijden, D.L. Lamm. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a combined analysis of the published results of randomized clinical trials. J Urol 168 (2002) (1964 - 1970)
- [37] A. Böhle, P.R. Bock. Intravesical bacillus Calmette-Guerin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 63 (2004) (682 - 687)
- [38] M. Huncharek, B. Kupelnick. Impact of intravesical chemotherapy versus BCG immunotherapy on recurrence of superficial transitional cell carcinoma of the bladder. Am J Clin Oncol 26 (2003) (402 - 407) Crossref.
- [39] M. Huncharek, B. Kupelnick. The influence of intravesical therapy on progression of superficial transitional cell carcinoma of the bladder: a meta-analytic comparison of chemotherapy versus bacilli Calmette-Guerin immunotherapy. Am J Clin Oncol 27 (2004) (522 - 528) Crossref.
- [40] D.L. Lamm, B.A. Blumenstein, J.D. Crissman, et al.. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 163 (2000) (1124 - 1129) Crossref.
- [41] A.R. Zlotta, J.P. van Vooren, K. Huygen, et al.. What is the optimal regimen for BCG intravesical therapy?. Eur Urol 37 (2000) (470 - 477) Crossref.
- [42] Martinez-Pineiro JA, Martinez-Pineiro L, Solsona E, et al. Club Urologico Espanol de Tratamiento Oncologico (CUETO). Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumours than the standard dose? Results of a prospective randomized trial. J Urol 2005; 174:1242–7.
- [43] A. Ojea, J.L. Nogueira, E. Solsona, 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 52 (2007) (1398 - 1406) Abstract, Full-text, PDF, Crossref.
- [44] A.P.M. Van der Meijden, R.J. Sylvester, W. Oosterlinck, W. Hoeltl, A.V. Bono. for the EORTC Genito-Urinary Tract Cancer Group. Maintenance bacillus Calmette-Guerin for Ta, T1 bladder tumors is not associated with increased toxicity: results from a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III Trial. Eur Urol 44 (2003) (429 - 434) Abstract, Full-text, PDF, Crossref.
- [45] H. Herr, G. Dalbagni. Defining bacillus Calmette-Guerin refractory superficial bladder tumours. J Urol 169 (2003) (1706 - 1708) Crossref.
- [46] R.J. Sylvester, A. van der Meijden, J.A. Witjes, et al.. High grade Ta urothelial carcinoma and carcinoma in situ of the bladder. Urology 66 (6 Suppl 1) (2005) (90 - 107) Crossref.
- [47] E. Solsona, I. Iborra, R. Dumont, J. Rubio-Briones, J. Casanova, S. Almenar. The 3-month clinical response to intravesical therapy as a predictive factor for progression in patients with high risk superficial bladder cancer. J Urol 164 (2000) (685 - 689)
- [48] G.V. Raj, H. Herr, A.M. Serio, et al.. Treatment paradigm shift may improve survival of patients with high risk superficial bladder cancer. J Urol 177 (2007) (1283 - 1286) Crossref.
- [49] O.N. Gofrit, D. Pode, A. Lazar, R. Katz, A. Shapiro. Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur Urol 49 (2006) (303 - 307) Abstract, Full-text, PDF, Crossref.
- [50] S. Holmang, S.L. Johansson. Stage Ta-T1 bladder cancer: the relationship between findings at first followup cystoscopy and subsequent recurrence and progression. J Urol 176 (2002) (1634 - 1637) Crossref.
Footnotes
a Department of Urology, General Teaching Hospital, First Faculty of Medicine, Charles University, Praha, Czech Republic
b Department of Urology, Ghent University Hospital, Ghent, Belgium
c EORTC Headquarters, Brussels, Belgium
d Department of Urology, Hyvinkää, Finland
e Department of Urology, Bad Schwartau, Germany
f Department of Urology, Fundació Puigvert, Universitat Autónoma de Barcelona, Spain
Corresponding author. Department of Urology, General Teaching Hospital, First Faculty of Medicine, Charles University, Ke Karlovu 6, Praha 2, 12808 Czech Republic. Tel. +420224967848; Fax: +420224967102.
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