Definitions for the levels of evidence (1a-4) and grades of recommendation (A-B) are provided at the end of the "Major Recommendations" field.
Epidemiology and Risk Factors
Conclusions
- The incidence of muscle invasive disease has not changed for a period of 5 years.
- Active and passive tobacco smoking continues to be the major risk factor while exposure-related incidence is decreasing (Level of evidence: 2a).
- The estimated male to female ratio was 3.8:1, with women more likely to be diagnosed with primary muscle invasive disease than men.
- Currently, treatment decisions cannot be based on molecular markers.
Recommendation
- The most important primary prevention for muscle-invasive bladder cancer is to eliminate active and passive smoking (Grade of recommendation: B).
Guidelines on Assessment of Tumour Specimens
Mandatory Evaluations
- Depth of invasion (categories pT2 vs pT3a, pT3b or pT4)
- Margins with special attention paid to the radial margin
- Histological subtype, if it has clinical implications
- Extensive lymph node representation (more than eight)
Optional Evaluations
- Bladder wall blood vessel invasion
- Pattern of muscle invasion
Diagnosis and Staging
Diagnosis
Recommendations for Primary Assessment of Presumably Invasive Bladder Tumours
- Renal and bladder ultrasonography, intravenous urography (IVU) or computed tomography (CT) prior to transurethral resection (TUR) (Grade of recommendation: B).
- Cystoscopy with description of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended (Grade of recommendation: C).
- TUR in one piece for small tumours (less than 1 cm), including a part from the underlying bladder muscle wall (Grade of recommendation: B).
- TUR infractions (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 non-papillary appearance or in case of fluorescence if photodynamic diagnosis (PDD) is used (Grade of recommendation: C).
- Biopsy of the prostatic urethra in the case of bladder neck tumour, when bladder carcinoma in situ (CIS) is present or suspected or when abnormalities of prostatic urethra are visible (Grade of recommendation: C).
- Careful inspection with histological evaluation of the bladder neck and urethral margin, either prior to or at the time of cystoscopy in women undergoing a subsequent orthotopic neobladder (Grade of recommendation: C).
- A second TUR at 2 to 6 weeks 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).
Imaging for Staging in Verified Bladder Tumours
Conclusions
- Diagnosis of invasive bladder cancer is made by cystoscopy and biopsy.
- Imaging is used for formal staging only if it will make a difference to the selection of treatment options.
- In all T1 tumours considered for conservative treatment, a second TUR is recommended before deciding on definite treatment (Grade of recommendation: B).
Recommendations for Staging
- For optimal local staging, either MRI with fast dynamic contrast-enhancement or MDCT with contrast enhancement are recommended for patients considered suitable for radical treatment (Grade of recommendation: B).
- For patients with confirmed muscle-invasive bladder cancer, multidetector-row CT(MDCT) of the chest, abdomen and pelvis is the optimal form of staging, including MDCT urography for complete examination of the upper urinary tracts. If MDCT is not available, lesser alternatives are excretory urography and a chest X-ray (Grade of recommendation: B).
Treatment Failure of Non-Muscle-Invasive Bladder Tumours
Recommendations
- In all T1 tumours at high risk of progression (such as high grade, multifocality, CIS present, and tumour size, as outlined in the non-muscle-invasive bladder cancer European Association of Urology [EAU] guideline) (See the National Guideline Clearinghouse [NGC] summary of the EAU Guidelines on TaT1 [non-muscle invasive] bladder cancer) immediate radical cystectomy is an option (Grade of recommendation: B).
- In all T1 patients failing intravesical therapy, cystectomy is an option. A delay in cystectomy increases the risk of progression and cancer-specific death (Grade of recommendation: B).
Neoadjuvant Chemotherapy
Conclusions
- Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival by 5 to 7% at 5 years (Level of evidence: 1a), irrespective of the type of definitive treatment used.
- Neoadjuvant chemotherapy has its limitations regarding patient selection, current development of surgical technique, and current chemotherapy combinations.
Recommendations
- Neoadjuvant cisplatin-containing combination chemotherapy should be considered in muscle-invasive bladder cancer, irrespective of definitive treatment (Grade of recommendation: A).
- Neoadjuvant chemotherapy is not recommended in patients with performance status (PS) >2 and impaired renal function (Grade of recommendation: B).
Radical Surgery and Urinary Diversion
Conclusions
- Cystectomy is the preferred curative treatment for localised bladder neoplasm (Level of evidence: 2)
- Radical cystectomy includes removal of regional lymph nodes, the extent of which has not been sufficiently defined (Level of evidence: 3)
- Radical cystectomy in both sexes must not include the removal of the entire urethra in all cases, which may then serve as outlet for an orthotopic bladder substitution (Level of evidence: 3)
- Terminal ileum and colon are the intestinal segments of choice for urinary diversion (Level of evidence: 3)
- The type of urinary diversion does not affect oncological outcome (Level of evidence: 3)
Recommendations for Radical Cystectomy
- Radical cystectomy in T2-T4a, N0-NX, M0, and high risk non-muscle invasive bladder cancer (BC) (see Treatment Failure of Non-Muscle-Invasive Bladder Tumors, above) (Grade of recommendation: B)
- No preoperative radiotherapy (Grade of recommendation: A)
- Lymph node dissection should be an integral part of cystectomy, extent not established (Grade of recommendation: B)
- Preservation of the urethra is reasonable if margins are negative. If no bladder substitution is attached the urethra must be checked regularly (Grade of recommendation: B)
- Laparoscopic and robot assisted laparoscopic cystectomy may be an option. Current data, however, have not sufficiently proven its advantages or disadvantages (Grade of recommendation: C).
Recommendations for Urinary Diversion
- Treatment is recommended at centers experienced in major types of diversion techniques and postoperative care (Grade of recommendation: B)
- Before cystectomy, the patient should be counselled adequately regarding all possible alternatives, and the final decision should be based on a consensus between patient and surgeon (Grade of recommendation: B).
- An orthotopic bladder substitute should be offered to male and female patients lacking any contraindications and who have no tumour in the urethra and at the level of urethral dissection (Grade of recommendation: B)
Non-Resectable Tumours
Conclusions
- Primary radical cystectomy in T4b bladder cancer is not a curative option.
- If there are symptoms, radical cystectomy may be a therapeutic/palliative option.
- Intestinal or non-intestinal forms of urinary diversion can be used with or without palliative cystectomy.
Recommendations
- For patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is not a curative option (Grade of recommendation: B).
- The indication for performing a palliative cystectomy is symptom relief.
- Morbidity of surgery and quality of life should be weighed against other options (Level of evidence: 3; Grade of recommendation: B/C).
Neo-Adjuvant Radiotherapy
Conclusions
- It is not proven that pre-operative radiotherapy for operable muscle-invasive bladder cancer increases survival (Level of evidence: 2).
- It is shown that pre-operative radiotherapy for operable muscle-invasive bladder cancer, using a dose of 45 to 50 Gy in fractions of 1.8 to 2 Gy results in down-staging after 4 to 6 weeks (Level of evidence: 2).
- Pre-operative radiotherapy with a dose of 45 to 50 Gy/1.8 to 2 Gy does not seem to significantly increase toxicity after surgery (Level of evidence: 3).
- There are suggestions in older literature that pre-operative radiotherapy will result in a decrease in local recurrence of muscle-invasive bladder cancer (Level of evidence: 3).
Recommendations
- Pre-operative radiotherapy is not recommended to improve survival (Grade of recommendation: B).
- Pre-operative radiotherapy for operable muscle-invasive bladder cancer results in tumour downstaging after 4 to 6 weeks (Grade of recommendation: A-C).
Bladder-Sparing Treatments
Transurethral Resection
Conclusion and Recommendation
TUR alone is not a curative treatment option in most patients (Level of evidence: 2a; Grade of recommendation: B).
External Beam Radiotherapy
Conclusions
- External beam radiotherapy alone should only be considered as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach (Level of evidence: 3).
- Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth (Level of evidence: 3).
Recommendation
- There is evidence that radiotherapy alone is less effective than curative therapy (surgery or trimodality treatment) (Grade or recommendation: B).
Chemotherapy
Conclusion
- With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and partial local responses have been reported (Level of evidence: 2b).
Recommendation
Chemotherapy alone is not recommended as primary therapy for localized bladder cancer (Grade of recommendation: A).
Multimodality Treatment
Conclusions
- A multimodality treatment approach shows a long-term survival rate comparable to that of primary treatment with radical cystectomy (Level of evidence: 3).
- Delay in surgical therapy can compromise survival rates. (Level of evidence: 2b).
Recommendations
- TUR alone is not a curative treatment option in most patients (Grade of recommendation: B).
- Radiotherapy alone is less effective than surgery (Grade of recommendation: B).
- Chemotherapy alone is not recommended as primary therapy for localized bladder cancer (Grade of recommendation: B).
- Multimodality treatment is an alternative in selected, well-informed and compliant patients where cystectomy is not considered for clinical or personal reasons (Grade of recommendation: B).
Adjuvant Chemotherapy
Conclusion
- Adjuvant chemotherapy is under debate. Neither randomized trials nor a meta-analysis have provided sufficient data to support the routine use of adjuvant chemotherapy (Level of evidence: 1a).
Recommendation
- Adjuvant chemotherapy is advised within clinical trials, but not for routine use because it has not been studied sufficiently (Grade of recommendation: A).
Metastatic Disease
Conclusions
- Urothelial carcinoma is a chemosensitive tumour.
- Performance status and the presence or absence of visceral metastases are independent prognostic factors for survival. These factors are at least as important as the type of chemotherapy administered (Level of evidence: 3).
- Cisplatin-containing combination chemotherapy is able to achieve a median survival of up to 14 months, with long-term disease-free survival reported in about 15% of patients with nodal disease and good PS (Level of evidence: 1b).
- Single-agent chemotherapy provides low response rates of usually short duration (Level of evidence: 2a).
- Carboplatin-combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of (complete response) CR and survival (Level of evidence: 2a).
- Non-platinum combination chemotherapy has produced substantial responses in first- and second-line use, but has not been tested against standard chemotherapy in fit patients or in a purely unfit patient group (Level of evidence: 2a).
- To date, there is no defined standard chemotherapy for 'unfit' patients with advanced or metastatic urothelial cancer (Level of evidence: 2b).
- Small-sized phase II trials provide evidence of moderate response rates for single agents or nonplatinum combinations at second-line use (Level of evidence: 2a).
- Post-chemotherapy surgery after a partial or complete response may contribute to long-term disease-free survival (Level of evidence: 3).
Recommendations
- Prognostic factors guide treatment selection (Grade of recommendation: B).
- First-line treatment for fit patients: use cisplatin-containing combination chemotherapy with gemcitabine plus cisplatin (GC), methotrexate/vinblastine/adriamycin/cisplatin (MVAC), preferably with granulocyte colony-stimulating factor (GCSF), or high-dose MVAC with GCSF (Grade of recommendation: A).
- Carboplatin and non-platinum combination chemotherapy as first-line treatment in patients fit for cisplatin is not recommended (Grade of recommendation: B).
- First-line treatment in patients unfit for cisplatin: use carboplatin combination chemotherapy or single agents (Grade of recommendation: C).
- Second-line treatment: consider single agents or paclitaxel/gemcitabine if the patient has a good PS (Grade of recommendation: C).
Quality of Life
Conclusions
- There is no randomized prospective health-related quality of life (HRQL) study evaluating different forms of definitive treatment for invasive bladder cancer.
- The overall HRQL after cystectomy remains good in most patients, whichever type of urinary diversion is used. Some data suggests that continent diversions produce a better HRQL (Level of evidence: 2b).
Recommendations
- HRQL in patients with muscle-invasive bladder cancer should be assessed using validated questionnaires (Grade of recommendation: A).
- Continent urinary diversions should be offered for reasons of HRQL, whenever a patient's age, personality, coping ability and tumour variables are suitable (Grade of recommendation: C).
Follow-Up
Conclusions and Recommendations According to Condition
| Condition |
Conclusion or Recommendation |
Level of Evidence or Grade of Recommendation |
| Secondary urethral tumour |
Staging and treatment should be done as for primary urethral tumour |
3 |
| For non-invasive tumour, local organ conservative treatment is advised |
C |
| In isolated invasive disease, a urethrectomy should be performed |
B |
| Urethral washes and cytology are not recommended for follow-up |
A |
| Pelvic recurrence |
The prognosis is poor
Treatment should be individualized depending on the local extent and symptoms
|
2b |
| Radiotherapy, chemotherapy and possibly surgery are options for treatment, either alone or in combination |
C |
| Upper urinary tract recurrence |
Specific upper urinary tract imaging is only indicated in case of clinical symptoms; radical nephroureterectomy can provide prolonged survival |
B |
General Recommendations for Follow-Up
This advice for follow-up is entirely based on expert opinion. General remarks are that follow-up should be dependent on the stage of the initial tumour after cystectomy. This means that the higher the initial tumour stage, the larger the chance for subsequent tumour recurrence. Non-oncological follow-up, for example monitoring of kidney function, seems indicated lifelong. After 5 years of follow-up, oncological surveillance may be stopped to be continued by functional surveillance.
At every visit, the following should be performed:
- History
- Physical examination
- Bone scan only when indicated
Definitions:
Levels of Evidence
1a Evidence obtained from meta-analysis of randomized trials
1b Evidence obtained from at least one randomized trial
2a Evidence obtained from one well-designed controlled study without randomization
2b Evidence obtained from at least one other type of well-designed quasi-experimental study
3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports
4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities
Grades of Recommendation
- Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomized trial
- Based on well-conducted clinical studies, but without randomized clinical trials
- Made despite the absence of directly applicable clinical studies of good quality
