Bladder

Disclaimer

This manual is not a substitute for consultation with an appropriate specialist.
The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.

1. Predisposing Factors/Prevention

Updated February 2008

Bladder cancer is the fifth most common and second most common genitourinary cancer diagnosis in British Columbia, affecting 30/100,000 men and 9/100,000 women.¹ It appears to be more common in Caucasians than people of African, Hispanic, Asian or First Nations origins.² Increasing age is also associated with increased incidence of bladder cancer.²

Cigarette smoking is one of the principal causes of bladder cancer and a strong association, with relative risks of three fold for long-term smokers, has been observed in a number of studies.³ Ionizing radiation is known to be a risk factor for bladder cancer, but because exposure at this site is rare, it is doubtful that it contributes significantly to incidence in Canada. Individuals whose source of drinking water for most of their lifetime is chlorinated surface water appear to have a slightly elevated risk.

Industrial and occupational exposures are thought to account for a significant proportion of bladder cancers among males. Workers exposed to 2-naphthylamine and benzidine have a 2-4 fold increased risk of bladder cancer, with risk residing mainly in those with high or prolonged exposure. Antioxidants containing 2-naphthylamine are used chiefly in the rubber industry. Leather workers and painters also have an elevated risk of bladder cancer. Aluminum workers exposed to polycyclic aromatic hydrocarbons in the pot room area have elevated risks for bladder cancer, and the Workers' Compensation Board of B.C. recognizes bladder cancer due to long term exposure to pot room fumes as a compensable illness.

All superscript references in this Chapter, refer to the list of References (Management section).

2. Screening/Early Detection

Updated February 2008

There are many screening tools for bladder cancer that are available, including urinalysis (microscopy or dip), urine cytology, or other urinary tests such as NMP-22, Immunocyt™, or BTA. The best use of these tests for routine screening for bladder cancer is currently unclear and thus not generally recommended as screening tests for the general population.

However, these tests, including urinalysis and urine cytology may be an efficient and cost effective method for screening high-risk groups including smokers and workers exposed to industrial toxins and patients who have a history of bladder cancer. Patients who exhibit hematuria, either overt or microscopic, should, as part of their initial investigation, undergo urine cytology examination.

Cytologic examination of urine may be useful among very high-risk groups (aluminium pot room workers), but the prevalence of preclinical bladder cancer is too low to make large-scale population screening practical.⁴

3. Diagnosis

Updated February 2008

Clinico-pathologic Considerations

Transurethral Resection (TUR)

The pathology report should include the following information:

Presence or absence of tumour
Growth pattern, papillary or flat
Tumour grade: low grade or high grade (note i, ii)
Invasion: lamina propria, submucosal, muscularis propria (note iii, iv, v)
Invasion of lymphatics, vascular or perineural spaces
Extension in to prostate, either along ducts or as a result of prostatic stromal infiltration
Presence or absence of urothelial carcinoma in-situ

Notes:

May be further classified as grade I, II, III
A mix of tumour grades may occur. The highest grade is the reported tumour grade
Submucosal indicates beyond the muscularis mucosa. It may be impossible to distinguish between muscularis propria and hypertrophic muscularis mucosa
Because submucosa may contain adipose tissue which may intermingle with muscularis propria, interpretation of perivesical soft tissue extension in TUR specimens may be difficult
If muscularis propria is identified, the depth of muscle invasion cannot generally be reliably determined in TUR specimens

Radical Cystectomy

Radical cystectomy specimens should be marked at all excision margins. Margins should be sampled generously. Obvious tumour should be sampled. Random sections of apparently normal mucosa should be sampled.

The pathology report should include the following information:

Presence or absence of tumour
Tumour grade: Low grade or High grade (may sub classify as grade I-III)
Number, location and size of tumours
Depth of invasion: lamina propria, submucosa, inner vs. outer muscularis propria involvement, extravesical extension
Involvement of ureters, urethra, prostate or seminal vesicles, uterus, vagina, pelvic wall, abdominal wall
Surgical margins: perivesical soft tissue, vesical serosal surface, ureteric, urethral
Invasion of lymphatics, vascular or perineural spaces
Lymph nodes: number positive, largest metastasis, extranodal extension with extent
High grade flat carcinoma in-situ (present/absent)
pTNM tumour stage

4. Staging

Updated March 2008

4.1 Classification Criteria

The classification applies only to carcinomas. Papilloma is excluded. There should be histological or cytological confirmation of the disease.

The following are the procedures for assessing T. N. and M categories:

T categories: Physical examination, imaging, and endoscopy
N categories: Physical examination and imaging
M categories: Physical examination and imaging

Regional Lymph Nodes

The regional lymph nodes are the nodes of the true pelvis, which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. Laterality does not affect the N classification.

TNM Clinical Classification 1997 (unchanged in 2002 update)

T- Primary Tumour

The suffix (m) should be added to the appropriate T category to indicate multiple tumours. The suffix (is) may be added to any T to indicate presence of associated carcinoma in situ.

TX	Primary tumour cannot be assessed
T0	No evidence of primary tumour
Ta	Noninvasive 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 (2-dimensional palpable mass)
T4	Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall
	T4a Tumour invades prostate or uterus or vagina
	T4b Tumour invades pelvic wall or abdominal wall

N - Regional 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

pTNM Pathological Classification

The pT, pN, and pM categories correspond to the T, N, and M categories.

G Histopathological Grading

GX	Grade of differentiation cannot be assessed
G1	Low grade
G2	Intermediate grade
G3	High grade

Stage Grouping

0a	Ta	N0	M0
0is	Tis	N0	M0
I	T1	N0	M0
II	T2a	N0	M0
	T2b	N0	M0
III	T3a	N0	M0
	T3b	N0	M0
	T4a	N0	M0
IV	T4b	N0	M0
	Any T	N1,2,3	M0
	Any T	Any N	M1

Pathologic Classification of Bladder Neoplasms

Non-invasive papillary urothelial carcinoma (low grade, high grade) 80%
Invasive urothelial carcinoma(Transitional cell carcinoma grade 1-3) 20%
Several subtypes with prognostic importance including micropapillary, sarcomatoid (spindle cell) and undifferentiated.
Urothelial carcinoma in-situ (Transitional cell carcinoma in-situ) 3%
Squamous cell carcinoma - 3 - 8% in Western world, 30% in Egypt.
Needs to be pure squamous cell carcinoma. If there is a component of urothelial carcinoma, invasive or in-situ, the tumour is classified as urothelial carcinoma with squamous differentiation.
Adenocarcinoma – 1% (Note: it is common to find glandular differentiation in TCC which does not constitute "bladder adenocarcinoma". All bladder adenocarcinomas are a diagnosis of exclusion of other primaries, especially colon, even if apparent adenocarcinoma in situ in bladder).
Small cell (neuroendocrine) carcinoma - 0.5-1% (56% pure, 46% combined with various other types)
Sarcoma – rare, careful exclusion of benign mimics is very important
The most recent WHO Classification of Tumours of the urinary system is an adaptation of the ISUP classification and is currently recommended. ⁽⁵⁾

4.2 Staging Diagram (PDF)

4.3 Investigations for Staging

History and physical examination
Routine blood work including CBC, creatinine, electrolytes, liver enzymes, alkaline phosphatase, and CEA ideally should be included for muscle-invasive disease.
Urinalysis, urine cytology
Assessment of upper tracts with IVP, CT or retrograde pyelograms.
Cystoscopy and examination under anesthesia
1. Complete description of the lesion (number, size, location, surface characteristics)
2. Bimanual examination prior to resection
3. Resection or at least deep cold cut biopsies of the lesion to include muscle
4. Bimanual examination after resection (essential for staging)
5. Description of bladder mucosa remote from the lesion and random biopsies
6. Measurement of bladder capacity
7. Biopsy of prostatic urethra if CIS, multi-centric bladder tumours or disease at the bladder neck
8. Examination of the prostate and biopsy of any abnormality
Metastatic work up: chest X-ray, CT scan of the abdomen and pelvis, and bone scan in symptomatic patients.
Clinico-pathologic staging: with the results of the above, the stage of bladder cancer can be assigned and appropriate management can be made. See staging diagram.

5. Management

1. Superficial Bladder Cancer (T1s, Ta, T1)
2. Muscle-Invasive Bladder Cancer (Stage T2a)
3. Deep Muscle Invasion (T2b), Perivesical Fat (T3), or Prostate Glandular Involvement (T4a)
4. Locally Advanced Bladder Cancer (T4b)
5. Metastatic Bladder Cancer
6. Less Common Histologies
References

Updated March 2008

Bladder cancer presents a clinical challenge, which requires multi-disciplinary efforts. Improvement in survival rate might be seen with improved preventive measures, earlier detection, as well as development of new therapeutic strategies to improve local control and to combat unrecognized micrometastases.

The most common histology is transitional cell carcinoma. Muscle-invasive bladder cancer often demands multi-disciplinary consideration and suitable cases may be referred to Urology Conference.

1. Superficial Bladder Cancer (T1s, Ta, T1)

Updated June 2008

Ta, T1 Low-Grade Tumour

All T1 bladder tumours require a re-resection to ensure adequate staging, as up to 25% of trans-urethral resections (TUR) specimens have been shown to be understaged. Thus, in general, all T1 bladder tumours require a re-resection, usually within four weeks.

After total transurethral resection of low-grade papillary tumour(s) confined to the basement membrane or superficial connective tissue, selected and random biopsies plus urine cytology may be performed to rule out carcinoma in situ.

Factors associated with increased risk of recurrence include: tumour grade (low grade vs. high grade, G1 vs. G2-3), stage (Ta versus T1), large size, multi-centricity, and a history of prior recurrence ⁽⁶⁾. Eighty percent of all patients with Ta low grade tumours who have no recurrence at the time of cystoscopy three months after diagnosis will have no recurrence after three years of follow-up. Conversely, 90% of patients with recurrent disease after three months continued to recur over the same time period.

If further biopsies are positive, superficial low-grade lesions too numerous to resect endoscopically, or recheck cystoscopies reveal recurrent low-grade superficial tumours, intravesical BCG immunotherapy may be administered (see GUBCG protocol).

Many trials of intravesical chemotherapy have demonstrated a decrease in the recurrence rate of superficial disease but the effect on the risk of muscle invasion, metastases, or cancer death remains uncertain ⁽⁷⁾, and physicians are cautioned that delay in performing cystectomy may be fatal.

Tis and High-Grade Ta, T1

Carcinoma in situ of the urothelium of the high-grade flat type is distinct from papillary in situ disease as it tends to behave more aggressively. Involvement of the urothelium ranges from a small focus to extensive disease throughout the bladder. The risk of progression to muscle invasive disease and subsequent metastases ranges from 40 to 80% with Tis depending on extent of disease.

Standard treatment is initial resection with or without perioperative chemotherapy (Mitomycin C). Post-operatively, patients should receive intravesical BCG after three to four weeks. Some retrospective series suggest that overall survival may be improved with early treatment with cystectomy for T1, Grade 3 cancers. Intravesical chemotherapy with BCG has been shown in a randomized trial to decrease the risk of invasive disease and metastatic disease in patients with high-grade Ta, T1 and highly selected cases of Tis⁽⁸⁾. Treatment of recurrent high-grade tumour with additional intravesical chemotherapy is potentially hazardous. One randomized trial of radiotherapy versus intravesical therapy after TUR demonstrated no relapse-free survival advantage with radiotherapy.

If BCG fails, cystectomy (and under some circumstances urethrectomy) with frozen section of the ureter is indicated. Tis does not respond reliably to radiotherapy.

Maintenance Therapy

There is one positive trial of maintenance using three week courses at 3, 6, 12, 18, 24, and 30 months⁽⁹⁾ (see GUBCG for details). Other trials have been negative using other regimes. There is no question that the toxicity of BCG escalates with repeated dosing in most patients and therefore toxicity should be carefully weighed.

BCG Failures

1. Patients with CIS or High grade (G3T1) disease at relapse

Treating such patients with any intravesical therapy is risky as they may lose their window of opportunity for surgical cure. Even 'effective' therapy at this point is likely only to delay the need for cystectomy by at most a year or two rather than prevent it. Some retrospective series suggest that overall survival may be improved with early treatment with cystectomy for T1 Grade 3 cancers.

Occasional patients who are not suitable surgical candidates because of age and/or co-morbid disease may be considered for further intravesical therapy. Low-dose BCG and interferon in a six week cycle followed by maintenance for three weeks at 5, 11, and 17 months is suggested.⁽¹⁰⁾ Combination interferon and BCG can be applied for by submission of an undesignated indication request for patients with refractory CIS or G3T1 disease who are not surgical candidates. It is important to note that powdered Interferon, reconstituted with sterile water be used, as the liquid preparation of interferon contains preservatives which destroys BCG. Those who fail such further measures early on will likely not respond to further intravesical therapy, and alternative measures should be considered urgently. Valrubicin appears less effective⁽¹¹⁾ and is currently neither available nor approved. Mitomycin C produces few responses and is not approved.⁽¹²⁾ If surgery is not possible referral for a Radiation Oncology opinion is a consideration.

2. Patients without CIS or High grade (G3) at relapse

Mitomycin C shows activity in some patients with BCG failure and may be worth a trial, but response rates are low (4 of 21 patients).⁽¹³⁾

3. Patients without CIS or High grade (G3) failing BCG.

Further surgical resection whenever the disease recurs is an option, as is cystectomy, but is troublesome for the patient and the surgeon especially when the disease becomes multifocal or inaccessible. Low-dose BCG and interferon has been reported ⁽¹⁴⁾ to have a 55% two year disease free survival in this setting and those whose disease seems to be progressing in stage, grade, or frequency may benefit.

One important exception is the micropapillary variant of TCC. If, after confirmation and review with the pathologist, micropapillary tumour is present, aggressive treatment should be considered even if diagnosed as clinical stage T1. This is an aggressive form of bladder cancer which usually requires aggressive treatment.

All superscript references in this chapter, refer to the list of References for Bladder.

2. Muscle-Invasive Bladder Cancer (Stage T2a)

Updated April 2008

Definitive single modality treatment with either cystectomy, or radiotherapy (with or without concurrent chemotherapy) are curative treatment options. Patients treated with radiotherapy must be followed closely cystoscopically if salvage cystectomy remains a viable option. Some patients may be eligible for a combined modality approach (see section 3). If a radical therapy is to be performed, ideally it should be initiated within four to six weeks, but no later than three months.

Conservative management of highly selected T2a lesions with completely resected small tumours and low and intermediate grade tumours with only superficial muscle invasion is a controversial practice requiring extreme caution and careful follow-up.

3. Deep Muscle Invasion (T2b), Perivesical Fat (T3), or Prostate Glandular Involvement (T4a)

Updated: April 2008

1. Radical Cystectomy

Radical cystectomy is the most frequent curative treatment option in North America with a five year survival range from 35% for patients with node-positive disease to up to 89% for T2 muscle-invasive disease. ⁽¹⁵⁾If a radical cystectomy is to be performed, ideally it should be initiated within 4-6 weeks, but no later than 3 months and should include an extended pelvic lymph node dissection.

2. External Beam Radiation Therapy

An alternative to cystectomy, external beam radiation therapy offers a potentially curative treatment approach with the possibility of bladder preservation. However, careful follow-up with cystectomy reserved for salvage is essential. It has been reported that between 15 and 25% of patients require salvage cystectomy for either recurrence or bladder contracture. ⁽¹⁶⁾ Single modality external beam radiation therapy is an option for patients whoa re interested in bladder preservation or who are unsuitable for surgery because of advanced age or concurrent medical problems. Five-year survival range for single modality external beam radiation therapy is 20-40% in large series.⁽¹⁷⁾ Some patients may be eligible for a combined modality approach (see below).

3. Combined Modality Therapy Including Chemotherapy

a) Neoadjuvant Chemotherapy

The rationale for giving chemotherapy before definitive treatment is to treat micrometastatic disease that may be present at diagnosis. In addition, chemotherapy is often better tolerated given before surgery or radical radiotherapy. A recent meta-analysis using updated data from 11 randomized controlled trials showed a 5% improvement in survival at five years (from 45% to 50%) with neoadjuvant platinum-based combination chemotherapy followed by surgery. ⁽¹⁸⁾ Appropriate patients have invasive urothelial carcinoma with no clinical evidence of nodal or metastatic disease who are to undergo a curative cystectomy, an ECOG performance status of 0 -1 and adequate renal function [stenting for hydronephrosis should be considered early] (see UGUNAJPG protocol).

b) Concurrent Chemotherapy and Radiotherapy

The role of concurrent chemo-radiotherapy is uncertain. The only randomized study of cisplatin concurrent chemotherapy was negative for survival, but did demonstrate improved local control. ⁽¹⁹⁾Multiple non-randomized studies demonstrate similar survival rates with tri-modality therapy to those found with radical cystectomy. This approach may be appropriate for selected patients who are interested in bladder preservation or who decline or are not suitable candidates for surgery. (see GUBPRT and GUBPWRT protocols)

c) Adjuvant Chemotherapy

A number of trials have been conducted comparing cystectomy alone to cystectomy with adjuvant chemotherapy. Many of these trials were underpowered, closed prematurely or used sub-optimal chemotherapy. An individual patient data meta-analysis has been done looking at the results of 491 patients from six trials.⁽²⁰⁾ The analysis showed a 25% relative risk reduction in death, however, the authors felt that the available data is too limited for a treatment decision to be based upon. Therefore, adjuvant chemotherapy is not routinely recommended. Patients should be enrolled in clinical trials whenever possible. Selected high risk patients (e.g. extravesical extension, node-positive) who are likely to tolerate platinum-based chemotherapy and who understand the limitations of the available data can be considered for treatment. (see UGUAJPG)

d) Tri-Modality Therapy

Bladder-sparing by means of 'tri-modality' therapy comprises aggressive TURBT followed by induction chemo-radiotherapy, cystoscopic reassessment with immediate cystectomy for those not in complete remission, and further chemoradiotherapy for those in remission.^{(21, 22)} Multiple non-randomized studies demonstrate similar survival rates with tri-modality therapy to those found with radical cystectomy. Patients considered for this approach must be compliant with frequent follow up visits. Individual cases should be presented at GU Conference for multi-modality consideration.

All superscript references in this chapter, refer to the list of References for Bladder.

4. Locally Advanced Bladder Cancer (T4b)

Updated: April 2008

Each case should be considered individually. Initial treatment with combination chemotherapy (GUAVPG) could be considered, followed by reassessment and further local measures if indicated. Alternatively, after consideration of the patient's age and general status, a course of concurrent chemo-radiotherapy (GUBPRT or GUBPWRT) or palliative irradiation may be recommended.

5. Metastatic Bladder Cancer

Updated: April 2008

Prior to the development of effective chemotherapy, the median survival with metastatic bladder cancer was three to six months. Combination chemotherapy has improved median survival to about 12 months. However, long-term survival remains rare.

Platinum-based combination chemotherapy (Gemcitabine with either Cisplatin or Carboplatin) may be recommended as initial treatment for patients with advanced invasive urothelial carcinoma with an ECOG performance status of 0-2 (refer to GUAVPG).⁽²³⁾ Patients responding well to systemic therapy should be considered for regional treatment on an individualized basis. Patients should be encouraged to take part in clinical trials whenever possible.

Palliative radiotherapy continues to be an effective modality for relief of symptoms from local and distant sites of disease.

6. Less Common Histologies

Published: April 2008

1. Squamous Cell Carcinomas

The most common cause of squamous cell carcinoma worldwide is schistosomal infections (bilharziasis). In Western countries where this infection is rare, squamous cell carcinoma is rare although an increased risk is associated with spinal cord injuries, especially those with indwelling catheters for ≥ 10 years.⁽²⁴⁾ Pure squamous cell carcinoma must be distinguished from transitional cell carcinoma with squamous differentiation. Most patients are diagnosed with advanced disease and have a poor prognosis.⁽²⁵⁾ Five-year survival rates are reported as 5% to 35% depending on the stage at diagnosis.

Radical cystectomy provides a survival rate, which to date has not been improved upon by any other treatment.⁽²⁶⁾ Patients tend to die of local recurrence but pre-operative radiotherapy seems to have little effect.⁽²⁷⁾No effective chemotherapy has been found.

2. Adenocarcinoma

Adenocarcinoma of the bladder is classified by its site of origin: primary, urachal or metastatic from local extension of a primary colon, prostate or ovarian cancer. As such, other primary cancers must be ruled out. Various histologic subtypes have been described for primary adenocarcinoma but their impact on prognosis is unknown.⁽²⁸⁾

Primary adenocarcinoma of the bladder has a poor prognosis with five-year survival rates reported in various series as 0% to 31%. Radical cystectomy is a reasonable management option as no other treatment option appears as successful to date. Patients with urachal adenocarcinoma should have an en bloc excision of the urachus and umbilicus with partial cystectomy. Radiotherapy is generally ineffective and there is limited experience with chemotherapy. Combination 5-fluorouracil-based chemotherapy as used for gastrointestinal adenocarcinoma has been tried with low response rates.⁽²⁹⁾

3. Small Cell Carcinoma

Small cell carcinomas are tumours of neuroendocrine origin that occur most commonly in the lungs. However, small cell carcinoma can occur in many other organs, including the urinary bladder. The best data for management of small cell carcinoma comes from experience with pulmonary small cell carcinomas.

Small cell carcinomas of the bladder usually present at an advanced stage and tend to be aggressive in their course. Two-thirds of patients present with metastatic disease which most commonly occurs in lymph nodes, liver, bones, lungs, and brain. Once a pathologic diagnosis of small cell carcinoma is made, patients should undergo a full metastatic work-up which includes CT scan of the abdomen and pelvis, chest x-ray, bone scan, and neurologic examination.⁽³⁰⁾ Chemotherapy is the mainstay of treatment. Patients who are well enough are treated with Cisplatin and Etoposide (see GUSCPERT protocol). Patients with localized disease can be treated with a combination of chemotherapy and radiotherapy ⁽³¹⁾ or chemotherapy followed by radical surgery.⁽³²⁾ For more frail patients, they can be treated palliatively with radiotherapy for local problems, or systemically with cyclophosphamide, doxorubicin and vincristine (as per LUCAV) or oral etoposide (as per LUPOE).

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Updated April 2008

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