What is bladder cancer?

Bladder cancer is a relatively common type of cancer in older adults, but patients have a good prognosis if their cancer is diagnosed and managed early

Bladder cancer is the ninth most common cancer worldwide, 11 and among the most expensive to manage. 10 The good news is that it has a relatively low mortality when compared with other cancers, particularly when it is detected and treated early. 44 It is important that bladder cancer is classified accurately as either non-muscle invasive or muscle invasive bladder cancer due to the fact that these stages of urothelial cancers are managed quite differently. 3, 11 There are a number of challenges when diagnosing bladder cancer, but technological advancements and new drugs are improving the accuracy of diagnosis and management through improved visualization for transurethral resection of the bladder tumor (TURBT). 3

A brief introduction to bladder cancer


There are different types of bladder cancer, and treatment strategies vary between types.

Urothelial or transitional cell carcinomas

  • About 90% of bladder cancers diagnosed in developed countries are urothelial or transitional cell carcinomas i.e. cancer of the cells lining the bladder and urothelium-lined urinary tract 2, 4
  • Urothelial carcinomas are the second most common urological malignancy and are one of the best understood neoplasms, with relatively well defined pathogenetic pathways, natural history, and tumor biology 45
  • Urothelial carcinomas can be non-muscle invasive or muscle invasive
Non-muscle invasive bladder cancer (NMIBC)

  • Approximately 75–85% of urothelial carcinomas are non-muscle invasive 2, 4 meaning cancer that has not grown beyond the cells lining the bladder or urinary tract
  • NMIBC usually appears as papillary tumors (small growths that look like mushrooms) confined to the mucosa or sub-mucosa, but also includes flat lesions (i.e. carcinoma in situ) 2
Muscle invasive bladder cancer (MIBC)

  • Muscle invasive bladder cancer is when the cancer has grown into the muscle layer of the bladder, or beyond, and this type needs more intensive treatment than NMIBC
  • Among patients treated with radical cystectomy because of MIBC, 43% had been initially diagnosed with NMIBC that progressed despite organ-preserving treatment 3
  • Approximately one-third of patients diagnosed with MIBC have undetected metastasis at the time of treatment of the primary tumor 3
Other types of bladder cancer

  • Squamous cell cancers are rare in the USA and Europe, representing less than 5% of cases 46

Key statistics

Epidemiology

Bladder cancer is the ninth most common cancer diagnosis worldwide, with more than 330,000 new cases each year and more than 130,000 deaths per year. 11 It is more common in older people and affects approximately four times the number of men than women. 3 The US National Cancer Institute estimates that there will be 72,570 new cases of bladder cancer in the US in 2013 and 15,210 deaths. 47

Although the incidence of bladder cancer is relatively high, the mortality is relatively low.

Men-world-inc-mortv2Women-world-inc-mort

Burden to healthcare systems

Bladder cancer is one of the most expensive cancers to manage, accounting for around 7% of total cancer expenditure in the US and this burden is comparable in other developed countries. Because of long-term survival and the need for lifelong routine monitoring and treatment, the cost per patient of bladder cancer from diagnosis to death ranges from US$96,000 to US$187,000 (2001 values) in the USA. Overall, bladder cancer is the fifth most expensive cancer in terms of total medical care expenditures, accounting for almost US$3.7 billion (2001 values) in direct costs. 8

Risk factors


In order of importance, the following factors are associated with an increased risk of bladder cancer:

Smoking48, 49

Smoking is the number one risk factor for bladder cancer, increasing the risk three-fold. It is the arylamines (mainly 4-aminobiphenyl and other heterocyclic amines) in cigarette smoke that are the responsible carcinogens. The risk increases following many years of smoking.
risk-factors

Occupational exposure to carcinogens3, 50

Chemical carcinogens e.g. benzene derivatives and arylamines used in the rubber and dye industry are also risk factors for developing bladder cancer, as are polycyclic aromatic hydrocarbons used in paint, aluminum, tar, and petrochemical industries. The risk is related to the metabolism of these carcinogens and a NAT2 (N-acetyltransferase 2) slow-acetylation genotype has been associated with increased risk of bladder cancer. 51

Gender52

Women are diagnosed less often than men, but tend to have more advanced disease at diagnosis as a result of the fact that bladder cancer is less often suspected.

Other factors

Radiotherapy:

people who have experienced external radiation are 1.42 times more likely to develop bladder cancer compared to the general population, and those who have experienced brachytherapy are 1.10 times more likely to develop bladder cancer. 53

Chemotherapy:

Certain chemotherapies have been shown to have carcinogenic effects, for example, cyclophosphamide used to treat non-Hodgkin lymphoma is an established bladder carcinogen. 54

Diet:

There does not appear to be a strong impact of diet, although vegetables and fruit seem protective. 55
Chronic infection: this risk factor is related to squamous invasive bladder cancer only. 46

Genetics:

Increasing evidence suggests that genetic predisposition has a significant influence on bladder cancer incidence. 3

Symptoms of bladder cancer


Blood in the urine (hematuria) is the most common finding in non-muscle invasive bladder cancer. Ta or T1 tumors do not cause bladder pain and rarely present with lower urinary tract symptoms. In patients who do complain of these symptoms, carcinoma in situ (CIS) might be suspected. 3

Bladder cancer classification

Overall classification of bladder cancer

bladder_for-banner-on-web

The diagram above shows the staging of bladder cancer, according to the current tumor, node, metastasis (TNM) classification. Tumors staged as CIS, Ta or T1 are non-muscle invasive bladder cancers (NMIBC). CIS is a flat non-invasive lesion. A Ta tumor is a non-invasive papillary tumor. A T1 tumor is a tumor that has invaded the sub-epithelial connective tissue. 3T2, T3a, T3b and T4 tumors are muscle invasive bladder cancers (MIBC). 3

It is important that bladder cancer is staged accurately as different management strategies are employed for non-muscle invasive bladder cancer compared with muscle invasive bladder cancer.

Bladder-tumors

Classification of non-muscle invasive bladder cancer (NMIBC)

In 1998, a new classification of non-invasive urothelial tumors was proposed by the World Health Organization (WHO) and the International Society of Urological Pathology (ISUP) and published by WHO in 2004. Its major contribution is a detailed histological description of the various grades, which uses specific cytological and architectural criteria. 3

1973 WHO GRADING 2004 WHO GRADING
Urothelial papilloma
Grade 1:

  • Well differentiated

Grade 2:

  • Moderately differentiated

Grade 3:

  • Poorly differentiated
Flat

  • Hyperplasia (flat lesion without atypia)
  • Reactive atypia (flat lesion with atypia)
  • Atypia of unknown significance
  • Urothelial dysplasia, Urothelial carcinoma in situ (CIS)

Papillary

  • Urothelial papilloma (benign lesion)
  • Papillary urothelial neoplasm of low malignant potential
  • Low-grade papillary urothelial carcinoma
  • High-grade papillary urothelial carcinoma

 

The new classification distinguishes between flat and papillary urothelial tumors:

Flat-and-papillary-lesions

The prognostic value of both grading systems (WHO 1973 and 2004) has been confirmed, but attempts to demonstrate better prognostic value of one system over another have yielded controversial results. The majority of clinical trials published to date on Ta or T1 bladder tumors have been performed using the 1973 WHO classification, and therefore the current European Association of Urology (EAU) guidelines are based on this scheme. Until the prognostic role of WHO 2004 is validated by more prospective trials, both classifications are currently used in practice. 3

Overview of management


As outlined in the overall classification section, accurate diagnosis between non-muscle invasive bladder cancer and muscle invasive bladder cancer is very important as they are treated differently.

The steps in management of bladder cancer are generally as follows: 311

Symptoms and signs

The most common finding in NMIBC is blood in the urine (hematuria). Lower urinary tract symptoms may appear where CIS is present.

Initial assessment

During initial assessment, use of voided urine cytology or urinary markers is advocated to predict high-grade tumor before TURBT. Cystoscopy is recommended in all patients with symptoms suggestive of bladder cancer and cannot be replaced by cytology or by any other non-invasive test.

Diagnosis/treatment

TURBT is the gold standard method to confirm diagnosis and treat non-muscle invasive bladder cancer with adjuvant chemotherapy or Bacillus Calmette-Guérin (BCG) in high-grade tumors. Treatment is dependent on whether the disease is non-muscle invasive or muscle invasive. Radical cystectomy is warranted in muscle invasive disease and systemic chemotherapy where there is evidence of metastases. In non-muscle invasive disease, if the tumor is high grade, TURBT followed by adjuvant intravesical chemotherapy/BCG is recommended.

Summary of management

Figuer-fra-symptom-til-action

Diagnosing bladder cancer


Early diagnosis of non-muscle invasive bladder cancer is essential to ensure timely treatment, which in turn minimizes the risk of recurrence or progression to muscle invasive disease.

The objectives of early diagnosis are:

To reduce mortality:

The prognosis for non-muscle invasive bladder cancer is excellent, providing the disease is diagnosed and managed early; 5-year survival rate of 97% for the earliest stage tumors. 56
To reduce the risk of recurrence: the probability of recurrence at 1 year ranges from 15% to 61%; at 5 years this ranges from 31% to 78%.57

To reduce the risk of progression:

the probability of progression from non-muscle invasive bladder cancer to muscle invasive bladder cancer at 1 year ranges from less than 1% to 17%; at 5 years this ranges from less than 1% to 45%. 2 This is particularly important for patients with carcinoma in situ (CIS), which can be difficult to detect.3

How is bladder cancer diagnosed?

The EAU guidelines include key recommendations for the diagnosis of non-muscle invasive bladder cancer. 3

RECOMMENDATION EVIDENCE GRADE
At the time of the initial diagnosis of bladder cancer, computed tomography (CT) urography or IVU should be performed only in selected cases (e.g. tumors located in the trigone) B
Cystoscopy is recommended in all patients with symptoms suggestive of bladder cancer. It cannot be replaced by cytology or by any other non-invasive test A
A one-piece TURBT is recommended for small papillary tumors (greater than 1 cm), including part of the underlying bladder wall B
A multiple fraction TURBT is recommended (including muscle tissue) for tumors >1 cm in diameter B
If equipment is available, fluorescence-guided biopsy should be performed instead of random biopsies when bladder CIS or high-grade tumor is suspected (e.g., positive cytology, recurrent tumor with previous history of a high-grade lesion) B
A second TURBT should be performed 2-6 weeks after the initial resection in the following situations: after incomplete initial TURB; if there is no muscle in the specimen after initial resection, with exception of Ta G1 tumors and primary CIS; in all T1 tumors; in all G3 tumors, except primary CIS A
The pathological report should specify tumor location, tumor grade, depth of tumor invasion, presence of CIS, and whether the detrusor muscle is present in the specimen A

Table footnote Evidence grade A = Based on clinical studies of good quality and consistency that addressed the specific recommendations, including at least one randomized trial. Evidence grade B = Based on well-conducted clinical studies, but without randomized clinical trials. Evidence grade C = Case-series study or extrapolations from level B studies.

Cystoscopy

anatomy-v1
Cystoscopy is considered the gold standard diagnostic tool for bladder cancer. Currently, white light cystoscopy is generally used. However, this procedure results in wide variations in the identification and resection of bladder cancer. 3, 58
Blue-light cystoscopy allows more sensitive fluorescence-guided biopsy and resection than conventional procedures leading to an additional detection rate of 20% for all tumors and 23% for CIS. 3

With Hexvix® blue-light cystoscopy, urologists are able to:

  • Detect small lesions in low-risk non-muscle invasive bladder cancer 58
  • Detect additional lesions in high-risk non-muscle invasive bladder cancer, particularly CIS 58

Transurethral resection of the bladder tumor (TURBT)

TURBT is both a diagnostic and therapeutic technique and any suspicion of bladder cancer warrants this procedure. 3, 59

The goal of TURBT in Ta or T1 bladder tumors is to make the correct diagnosis and remove all visible lesions. 3ics

A complete and correct TURBT is essential for the prognosis of the patient. Unfortunately, they are often incomplete. The most important risk factor for understaging T1 tumors is absence of muscle in the tissue which occurs in 30–50% of submitted specimens. Understaging of muscle invasive bladder cancer occurs in 10% of cases. Serious adverse events are rare in TURBT, but can include occasional bleeding and perforation (greater than 5%). It should also be noted that CIS cannot be resolved by endoscopic procedures (i.e. TURBT) alone. 3, 60

What are the challenges of diagnosis?

Early recurrence may be due to missed tumors on cystoscopy and/or incomplete initial resection. 3, 4, 60 10–20% of tumors are missed with white light cystoscopy alone,[Mostafid, 2012] residual tumors being found in 49-70% of cases on repeat resection. 15, 61
As a result of inadequate diagnosis, patients require repeat procedures (cystoscopy and resection, with local or general anesthesia) to manage recurrent disease, further increasing the risk of surgical complications 62 and increased costs.

Compared to white light cystoscopy alone, Hexvix® blue-light cystoscopy improves detection of non-muscle invasive bladder cancer because more lesions are detected, and improves removal of tumors during resection due to better visualization.12, 13 This results in an improved surgical outcome, leading to fewer residual tumors, 13, 15 and fewer short- and long-term recurrences. 12


Treating bladder cancer

General principles

The general principles of bladder cancer treatment are outlined below. 3, 64

general-treatment-principles

Adjuvant treatment options

Following TURBT, adjuvant treatment options include early instillation chemotherapy (defined as chemotherapy within 6 hours of TURBT), further instillation chemotherapy, instillation of BCG, and radical cystectomy. The choice of therapy depends on the stage of disease and treatment goals. 3, 11, 65

Treatment-options_28.02.14

EAU guidelines for adjuvant therapy in Ta or T1 tumors and in CIS are summarized below.3

 

RECOMMMENDATION EVIDENCE GRADE
Low risk of tumor recurrence and progression, one immediate instillation of chemotherapy is recommended as the complete adjuvant treatment A
Intermediate-risk Ta T1 tumors, one immediate instillation of chemotherapy should be followed by 1 year full-dose BCG treatment, or by further instillation of chemotherapy for a maximum of 1 year A
High-risk tumors, full-dose intravesical BCG for 1-3 years is indicated A
In patients with CIS in the epithelial lining of the prostatic urethra, transurethral resection of the bladder (TURBT) followed by intravesical instillations of BCG may be a suitable option C
For patients at high risk of tumor progression, immediate radical cystectomy may be offered C
Radical cystectomy is recommended for patients with BCG failure B

Table footnote: Evidence grade A = Based on clinical studies of good quality and consistency that addressed the specific recommendations, including at least one randomized trial. Evidence grade B = Based on well-conducted clinical studies, but without randomized clinical trials. Evidence grade C = Case-series study or extrapolations from level B studies.