At initial diagnosis, 30% of bladder cancer cases are already diagnosed as muscle-invasive disease (MIBC). Tobacco smoking is the best established as well as the principal preventable risk factor for bladder cancer. It accounts for 50–65% of male cases and 20–30% of female cases.4 The other risk factors include occupational exposure to certain chemicals, previous radiotherapy, bladder schistosomiasis, chronic urinary tract infections, previous chemotherapy and potentially dietary factors.
Women were more likely to be diagnosed with primary muscle-invasive disease than men (85% versus 51%).2 It has also been suggested that women are more likely to be older than men at diagnosis. In addition, delayed diagnosis is more likely in women with haematuria.5
Painless haematuria is the commonest presenting symptom. Patients may also present with urgency, increased urinary frequency and dysuria. In cases with advanced disease, there may be pelvic pain, symptoms of urinary tract obstruction, lymphoedema and bone pain. Initial flexible cystoscopy remains the gold standard test for diagnosis of bladder tumours. However, rectal/vaginal bimanual examination becomes important in MIBC to assess for thickening or mobile versus fixed pelvic mass. At initial cystoscopy, it is crucial to document a careful description of the findings including site, size, number and appearance of tumour/s as well as any other mucosal abnormalities seen. Use of a bladder diagram is strongly recommended.
Role of initial TURBT
Trans-Urethral Resection of Bladder Tumour (TURBT) is the mainstay of diagnosing MIBC. The goals of TURBT are:
• Obtain tissue for histopathological diagnosis
• Obtain staging of tumour ie. whether muscle involved
• Obtain grade of tumour
• Obtain macroscopic clearance where possible.
Bimanual examination of bladder under anaesthesia (EUA), both pre- and post-resection is mandatory though there is some discrepancy between EUA and T-stage after cystectomy—11% clinical overstaging versus 31% clinical understaging.6 If the tumour is located on the trigone or bladder neck, if there is CIS or if there are multiple tumours, there is a higher risk of prostatic urethral/ductal involvement.7,8 There is a 33–53% risk of residual disease after initial TURBT and a 4–25% risk of tumour understaging as non-muscle invasive.9,10 Also, 25–46% of patients undergoing radical cystectomy were found to have concomitant prostate cancer on histology.11,12 Therefore it is important to look for prostate cancer in patients with bladder cancer.
Imaging to stage MIBC
Tumour stage and grade determine further treatment as well as prognosis in MIBC. Imaging to stage MIBC looks for:
• Extent of local tumour extension
• Lymph nodal (LN) involvement
• Spread of tumour to upper urinary tracts and distant metastases.
CT of chest, abdomen and pelvis with an excretory urogram phase is the recommended imaging for staging MIBC.13 LN involvement simply based on size has its limitations as metastases could also exist in normal-sized LNs. The sensitivity and specificity of detecting LN metastases is low, ranging from 48–87%. However, the criteria for significantly enlarged LNs as measured on CT or MRI is >8mm for pelvic LNs and >10mm for abdominal LNs in a maximum short-axis diameter.14,15 Bone scan and imaging of the brain are not recommended routinely as bone and brain metastasis at presentation are rare. There are studies looking at FDG-PET/CT imaging for staging metastatic bladder cancer but there isn’t enough evidence to use it currently.
Role of neoadjuvant chemotherapy
With standard radical cystectomy alone, the five-year survival in MIBC is about 50% only. Therefore neo-adjuvant chemotherapy has been extensively investigated with different regimes and chemotherapeutic agents. What has been shown is that neoadjuvant cisplatin-containing combination chemotherapy improves overall survival and the current chemotherapy regime is Gemcitabine-Cisplatin, which has a similar survival advantage as that of MVAC (previously used regime) with better tolerability and safety profiles.16 With neoadjuvant chemotherapy, there is a 16% risk reduction of death, 5% absolute benefit in overall survival at five years (45% to 50%) and 6% improvement in overall survival at 10 years (30% to 36%) but no benefit for locoregional control and locoregional disease-free survival.17,18
Though adjuvant chemotherapy has the advantage of being given after accurate pathological staging and avoiding delay in definitive treatment, the in-vivo chemosensitivity of the tumour cannot be assessed and quite often, the chemotherapy is delayed due to post-operative morbidity. Adjuvant chemotherapy is not routinely recommended in current clinical practice due to lack of sufficient data and still remains under investigation.
Neoadjuvant radiotherapy—is it any good?
The use of neoadjuvant radiotherapy has been looked into in an effort to improve surgical outcomes and survival. 45 Gy of radiotherapy in the neoadjuvant setting did show a significant increase in pathological complete response from 9% to 34% but did not show a significant increase in five-year survival.19 It also does not significantly increase toxicity after surgery. Neoadjuvant radiotherapy for T1–T3 tumours showed a downstaging to T0 after cystectomy in 57% of patients (cf 7% without radiotherapy) and specifically in the T3 group, that was 59% (cf 0%) in a small study.20 However, in current practice, there is no role for pre-operative radiotherapy for patients with operable muscle-invasive bladder cancer as it has not been shown to increase survival.
Radical cystectomy remains the standard curative treatment of choice for localised MIBC in most parts of the western world.21 However, the timing of radical cystectomy is crucial. Patients treated >90 days after original diagnosis were noted to have a significant increase in extravesical disease (81 versus 52%).22 Recurrence-free survival and OS were also noted to be significantly better in patients with cystectomy <90 days from diagnosis.23
The traditional indication for radical cystectomy is T2-4a, N0-Nx, M0 disease. Cystectomy carries with it a mortality rate of 3% and morbidity rate of 30%. These complications may be related to pre-existing medical conditions as well as to the surgical procedure itself, the bowel anastomosis and the type of urinary diversion.
Risk factors for morbidity with cystectomy:24
• Advanced age (biological rather than chronological)
• Prior abdominal surgery
• Extravesical disease
• Prior radiotherapy.
In men, standard surgery includes removal of the bladder, prostate, seminal vesicles, distal ureters and regional LNs whereas in women, it includes removal of bladder, entire urethra and adjacent vagina, uterus, distal ureters and regional LNs.25 Lymph node dissection (LND) is an integral part of cystectomy. Extended LND, as opposed to standard/limited LND, has shown survival benefit post-radical cystectomy.26 These procedures are performed in a centralised fashion in high-volume centres as it reduces morbidity and mortality rates. Laparoscopic and robotic-assisted laparoscopic cystectomy is feasible in both male and female patients. Laparoscopic cystectomy is a technically challenging procedure with a high learning curve and requires a high level of skill. However, the patients still have lesser blood loss, time to oral intake, analgesic requirements and shorter length of hospital stay.27
Urinary diversion after cystectomy can be broadly divided into three anatomical groups:
1. Abdominal diversions eg. ureterocutaneostomy, ileal/colonic conduit and various forms of continent pouches.
2. Urethral diversions eg. various forms of gastrointestinal pouches anastomosed to urethra to fashion a continent orthotopic diversion.
3. Rectosigmoid diversion eg. ureterosigmoidostomy and uretero-(ileo)-rectostomy.
The choice of urinary diversion has not shown to affect the oncological outcomes of cystectomy. Factors determining surgical outcomes however include:
• Age and comorbidities, previous treatments for bladder cancer
• Other pelvic diseases
• Surgeon and hospital volumes of cystectomy
• Type of urinary diversion.
Five-year overall survival post-radical cystectomy is reported at 45% and cancer-specific survival is 62%.28 Recurrence-free survival at five years is 68% and at 10 years is 66% though for node-positive disease, the five-year rate is significantly reduced to 34–43%.29
Radical external beam radiotherapy
External beam radiotherapy (EBRT) is an alternative to radical cystectomy for curative treatment of MIBC. The target field in males is bladder and prostatic urethra and in females the bladder only with a 1.5–2cm safety margin to allow for organ movements.30 Any larger field has not been shown to have any benefit. The target dose is usually 60–66 Gy in fractions of 1.8–2 Gy daily and should not exceed 6–7 weeks. Using modern EBRT techniques, the major radiotherapy-related late bladder/bowel complication rates are <5%. Overall five-year survival rates with EBRT are 30–60% and cancer-specific survival rates are 20–50%.31 Important prognostic factors include:
• Response to EBRT
• Tumour size
• Completeness of initial TURBT.
However, a Cochrane analysis has shown radical cystectomy to have an overall survival advantage over EBRT.32 Therefore EBRT alone as a therapeutic option should only be considered when a patient is not fit for cystectomy or as a multimodality bladder-preserving approach.
Organ-preserving strategies have been suggested as alternatives to radical cystectomy for carefully selected, well-informed and compliant patients. The rationale of such approaches is to achieve local tumour control. Systemic chemotherapy is aimed at eradicating micrometastases. Five-year survival rates of 70% have been reported with multi-modality bladder-preserving treatment. TURBT or chemotherapy alone however cannot be offered as a standard curative or primary treatment for MIBC. These patients require very close follow up with meticulous surveillance and multiple invasive procedures. The risk of LN involvement when cystectomy is required is about 25%.
Management of metastic bladder cancer
About 50% of patients relapse after radical cystectomy of which 70% are distant metastases. 10–15% are already metastatic at diagnosis.33 Prior to effective platinum-based chemotherapy, these patients rarely had a median survival of >3–6 months. Platinum-based chemotherapy has become the mainstay treatment in metastatic bladder cancer.
Patients are generally deemed unfit for cisplatin-based chemotherapy if their GFR is <60mL/min and performance status is >2.34 Renal function assessment is vital in patients with bladder cancer. >50% of patients with urothelial cancer are deemed unfit for cisplatin-based chemotherapy.35
For patients with LN but not other metastases, good performance status and good renal function, excellent response rates have been achieved with up to 20% of patients achieving long-term disease-free survival and surgery may be considered in selected patients to confer better disease-free survival.36 30–40% of patients with advanced or mBC have bone metastases. Skeletal-related events due to bone metastases confer poorer quality of life and increased mortality.37 Zoledronic acid or denosumab is recommended for treatment of metastases in mBC.
Conflict of interest: none declared
1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol 2009 Jun; 27(3):289-93
2. Vaidya A, Soloway MS, Hawke C, et al. De novo muscle invasive bladder cancer: is there a change in trend? J Urol 2001 Jan; 165(1):47-50
3. Prout GR Jr, Griffin PP, Shipley WU. Bladder carcinoma as a systemic disease. Cancer 1979 Jun; 43(6):2532-9
4. Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA 2011 Aug 17; 306(7):737-45
5. Cardenas-Turanzas M, Cooksley C, Pettaway CA, et al. Comparative outcomes of bladder cancer. Obstet Gynecol 2006 Jul; 108(1):169-75
6. Ploeg M, Kiemeney LA, Smits GA, et al. Discrepancy between clinical staging through bimanual palpation and pathological staging after cystectomy. Urol Oncol 2012 May-Jun; 30(3):247-51
7. Matzkin H, Soloway MS, Hardeman S. Transitional cell carcinoma of the prostate. J Urol 1991 Nov; 146(5):1207-12
8. Mungan MU, Canda AE, Tuzel E, et al. Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder. Eur Urol 2005 Nov; 48(5):760-3
9. Jakse G, Algaba F, Malmstrom PU, et al. A second-look TUR in T1 transitional cell carcinoma: why? Eur Urol 2004 My; 45(5):539-46
10. Brauers A, Buettner R, Jakse G. Second resection and prognosis of primary high risk-superficial bladder cancer: is cystectomy often too early? J Urol 2001 Mar; 165(3):808-10
11. Damiano R, Di Lorenzo G, Cantiello F, et al. Clinicopathological features of prostate adenocarcinoma incidentally discovered at the time of radical cystectomy: an evidence-based analysis. Eur Urol 2007 Sep; 52(2):648-57.
12. Gakis G, Schilling D, Bedke J, et al. Incidental prostate cancer at radical cystoprostatectomy: implications for apex-sparing surgery. BJU Int 2010 Feb; 105(4);468-71
13. http://www.uroweb.org/gls/pdf/07_Bladder%20Cancer_LRV2.pdf EAU guidelines.
14. Barentsz JO, Engelbrecht MR, Witjes JA, et al. MR imaging of the male pelvis. Eur Radiol 1999; 9(9):1722-36
15. Dorfman RE, Alpern MB, Gross BH, et al. Upper abdominal lymph nodes: criteria for normal size determined with CT. Radiology 1991 Aug; 180(2):319-22
16. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, et al. Gemcitabine and Cisplatin versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter Phase III Study. J Clin Oncol 2000 Sep; 18(17):3068-77
17. Advanced Blader Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003 Jun; 36(9373):1927-34
18. International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; Australian Bladder Cancer Study Group; National Cancer Institute of Canada Clinical Trials Group; Finnbladder; Norwegian Bladder Cancer Study Group; Club Urologico Espanol de Tratamiento Oncologico Group, Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing neoadjuvant cisplatin methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011 Jun; 29(16):2171-7
19. Slack NH, Bross ID, Prout GR. Five-year follow-up results of a collaborative study of therapies for carcinoma of the bladder. J Surg Oncol 1977; 9(4):393-405
20. Granfors T. Tomic R, Ljungberg B. Downstaging and survival benefits of neoadjuvant radiotherapy before cystectomy for patients with invasive bladder carcinoma. Scand J Urol Nephrol 2009; 43(4):293-9
21. WHO Consensus Conference in Bladder Cancer, Hautmann RE, Abol-Enein H, Hafez K, Haro I, Mansson W, Mills RD, Montie JD, Sagalowsky AI, Stein JP, Stenzl A, Studer UE, Volkmer BG. Urinary diversion. Urology 2007 Jan; 69(1 Suppl):17-49.
22. Chang SS, Hassan JM, Cookson MS et al. Delaying radical cystectomy for muscle invasive bladder cancer results in worse pathological stage. J Urol 2003 Oct; 170(4 Pt 1):1085-7.
23. Sanchez-Ortiz RF, Huang WC, Mick R, et al. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 2003 Jan; 169 (1):110-5
24. Lawrentschuk N, Colombo R, Hakenberg OW, et al. Prevention and management of complications following radical cystectomy for bladder cancer. Eur Urol 2010 Jun; 57(6):914-21.
25. Stenzl A, Nagele U, Kuczyk M, et al. Cystectomy: technical considerations in male and female patients. EAU Update Series 2005 Sep; 3:138-46.
26. Koppie TM, Vickers AJ, Vora K, et al. Standardization of pelvic lymphadenectomy performed at radical cystectomy: can we establish a minimum number of lymph nodes that should be removed? Cancer 2006 Nov; 107(10):2368-74.
27. Aboumarzouk OM, Hughes O, Narhari K, et al. Safety and feasibility of Laparoscopic Radical Cystectomy for the treatment of bladder cancer. J Endourol 2013 Sep; 27(9):1083-95.
28. Nuhn P, May M, Sun M, et al. External validation of postoperative nomograms for prediction of all-cause mortality, cancer-specific mortality, and recurrence in patients with urothelial carcinoma of the bladder. Eur Urol 2012 Jan; 61(1):58-64.
29. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001 Feb; 19(3):666-75.
30. Gospodarowicz MK, Quilty PM, Scalliet P, et al. The place of radiation therapy as definitive treatment of bladder cancer. Int J Urol 1995 Jun; 2(Suppl 2):41-8
31. De Nee W, Lybeert ML, Goor C, et al, Ribot JG. Radiotherapy for T2 and T3 carcinoma of the bladder: the influence of overall treatment time. Radiother Oncol 1995 Sep; 36(3):183-8
32. Shelley MD, Barber J, Wilt T, et al. Surgery versus radiotherapy for muscle invasive bladder cancer. Cochrane Database Syst Rev 2002; (1):CD002079
33. Rosenberg JE, Carroll PR, Small EJ. Update on chemotherapy for advanced bladder cancer. J Urol 2005 Jul; 174(1):14-20
34. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer ‘unfit’ for cisplatin-based chemotherapy: phase II-results of EORTC study 30986. J Clin Oncol 2009 Nov 20; 27(33):5634-9
35. Dash A, Galsky MD, Vickers AJ, et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patient with urothelial carcinoma of the bladder. Cancer 2006 Aug; 107(3):506-13
36. Herr HW, Donat SM, Bajorin DF. Post-chemotherapy surgery in patients with unresectable or regionally metastatic bladder cancer. J Urol 2001 Mar; 165(3):811-4
37. Aapro M, Abrahamsson PA, Body JJ, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008 Mar; 19(3):420-32