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Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder.[1] It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body.[6][7] Symptoms include blood in the urine, pain with urination, and low back pain.[1]

Bladder cancer
TransCellCaMark.png
Transitional cell carcinoma of the bladder. The white in the bladder is contrast.
SpecialtyOncology
SymptomsBlood in the urine, pain with urination[1]
Usual onset65 to 84 years old[2]
TypesTransitional cell carcinoma, squamous cell carcinoma, adenocarcinoma[3]
Risk factorsSmoking, family history, prior radiation therapy, frequent bladder infections, certain chemicals[1]
Diagnostic methodCystoscopy with tissue biopsies[4]
TreatmentSurgery, radiation therapy, chemotherapy, immunotherapy[1]
PrognosisFive-year survival rates ~77% (US)[2]
Frequency549,000 new cases (2018)[5]
Deaths200,000 (2018)[5]

Risk factors for bladder cancer include smoking, family history, prior radiation therapy, frequent bladder infections, and exposure to certain chemicals.[1] The most common type is transitional cell carcinoma.[3] Other types include squamous cell carcinoma and adenocarcinoma.[3] Diagnosis is typically by cystoscopy with tissue biopsies.[4] Staging of the cancer is determined by transurethral resection and medical imaging.[1][8][9]

Treatment depends on the stage of the cancer.[1] It may include some combination of surgery, radiation therapy, chemotherapy, or immunotherapy.[1] Surgical options may include transurethral resection, partial or complete removal of the bladder, or urinary diversion.[1] The typical five-year survival rates in the United States is 77%, Canada is 75%, and Europe is 68%.[2][10][11]

Bladder cancer, as of 2018, affected about 1.6 million people globally with 549,000 new cases and 200,000 deaths.[5] Age of onset is most often between 65 and 84 years of age.[2] Males are more often affected than females.[2] In 2018, the highest rate of bladder cancer occurred in Southern and Western Europe followed by North America with rates of 15, 13, and 12 cases per 100,000 people.[5] The highest rates of bladder cancer deaths were seen in Northern Africa and Western Asia followed by Southern Europe.[5]

Signs and symptomsEdit

 
Location of bladder cancer

Bladder cancer characteristically causes blood in the urine (hematuria), which may be visible (gross/macroscopic hematuria) or detectable only by microscope (microscopic hematuria). Blood in the urine is the most common symptom in bladder cancer, and is painless. Visible blood in the urine may be of only short duration, and a urine test may be required to confirm non visible blood. Between 80–90% of people with bladder cancer initially presented with visible blood.[12] Blood in the urine may also be caused by other conditions, such as bladder or ureteric stones, infection, kidney disease, kidney cancers or vascular malformations, though these conditions (except kidney cancers) would typically be painful.

Other possible symptoms include pain during urination (dysuria), frequent urination, or feeling the need to urinate without being able to do so. These signs and symptoms are not specific to bladder cancer, and may also be caused by non-cancerous conditions, including prostate infections, overactive bladder or cystitis.

Patients with advanced disease refer pelvic or bony pain, lower-extremity swelling, or flank pain. Rarely, a palpable mass can be detected on physical examination.

CausesEdit

Tobacco smoking is the main known contributor to urinary bladder cancer; in most populations, smoking is associated with over half of bladder cancer cases in men and one-third of cases among women,[13] however these proportions have reduced over recent years since there are fewer smokers in Europe and North America.[14] There is an almost linear relationship between smoking duration (in years), pack years and bladder cancer risk. A risk plateau at smoking about 15 cigarettes a day can be observed (meaning that those who smoke 15 cigarettes a day are approximately at the same risk as those smoking 30 cigarettes a day). Quitting smoking reduces the risk, however former smokers will most likely always be at a higher risk of bladder cancer compared to people who have never smoked.[14] Passive smoking does not appear to be a risk.[15]

Thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens such as benzidine. 2-Naphthylamine, which is found in cigarette smoke, has also been shown to increase bladder cancer risk. Occupational or circumstantial exposure to the following substances has also been implicated as a cause of bladder cancer; 4-aminobiphenyl (rubber industry), β-naphtylamine (rubber industry), phenacetin (analgesic), arsenic in drinking water, auramine (dye manufacturing), magenta (dye manufacturing), ortho-toluidine (dye manufacturing), epoxy and polyurethane resin hardening agents (plastics industry), chlornaphazine, coal-tar pitch.[16][17][18][19] Occupations at risk are bus drivers, rubber workers, painters, motor mechanics, leather (including shoe) workers, blacksmiths, machine setters, and mechanics.[20][21] Hairdressers are thought to be at risk as well because of their frequent exposure to permanent hair dyes.[22]

Infection with Schistosoma haematobium (bilharzia or schistosomiasis) may cause bladder cancer, specially of the squamous cell type.[23] Schistosoma eggs induces a chronic inflammatory state in the bladder wall resulting in tissue fibrosis.[24] Higher levels of N-nitroso compounds(nitrate) has been detected in urine samples of people with schistosomiasis.[25] N-Nitroso compounds have been implicated in the pathogenesis of schistosomiasis related bladder cancer. They are known to cause alkylation DNA damage, specially Guanine to Adenine transition mutations in the H-ras and p53 tumor suppressor gene.[26] Mutations of p53 are detected in 73% of the tumors, BCL-2 mutations accounting for 32% and the combination of the two accounting for 13%.[27] Other causes of squamous cell carcinoma of the bladder include chronic catheterizations in people with a spinal cord injury.[28]

In addition to these major risk factors there are also numerous other modifiable factors that are less strongly (i.e. 10–20% risk increase) associated with bladder cancer, for example, obesity.[29] Although these could be considered as minor effects, risk reduction in the general population could still be achieved by reducing the prevalence of a number of smaller risk factor together.[30]

It has been suggested that mutations at HRAS,PIK3CA, TERT, KRAS2, RB1, TSC1 and FGFR3 may be associated in some cases.[31][32] Deletions of parts or whole of chromosome 9 is common in bladder cancer.[33] Low grade cancer are known to harbor mutations in RAS pathway (15%) and the fibroblast growth factor receptor 3 (FGFR3) gene (60%), both of which play a role in MAPK pathway. p53 and RB gene mutations are implicated in high-grade muscle invasive tumors.[34] 89% of muscle invasive cancers have shown mutations in chromatin-remodelling and histone modifying genes.[35] Deletion of both copies of the GSTM1 gene has a modest increase in risk of bladder cancer. GSTM1 gene product glutathione S-transferase M1 (GSTM1) participates in the detoxification process of carcinogens such as polycyclic aromatic hydrocarbons found in cigarette smoke.[36] Similarly, mutations in NAT2 (n-acetyltransferase) is associated with increased risk for bladder cancer. N-acetyltransferase helps in detoxification of carcinogens such as aromatic amines (also present in cigarette smoke).[37]

DiagnosisEdit

 
Bladder wall thickening due to cancer
 
Bladder tumor in FDG PET due to the high physiological FDG-concentration in the bladder, furosemide was supplied together with 200 MBq FDG. The uptake cranial to the lesion is a physiological uptake in the colon.

Currently, the best diagnosis of the state of the bladder is by way of cystoscopy, which is a procedure in which a flexible or rigid tube (called a cystoscope) bearing a camera and various instruments is introduced into the bladder through the urethra. The flexible procedure allows for a visual inspection of the bladder, for minor remedial work to be undertaken and for samples of suspicious lesions to be taken for a biopsy. A rigid cystoscope is used under general anesthesia in the operating room and can support remedial work and biopsies as well as more extensive tumor removal. Unlike papillary lesion, which grow into the bladder cavity and are readily visible, carcinoma in situ lesion are flat and obscure. Detection of carcinoma in situ lesions requires multiple biopsies from different areas of interior bladder wall.[38] Photodynamic detection (blue light cystoscopy) can aid in the detection of carcinoma in situ. In photodynamic detection, a dye is instilled into the bladder with the help of a catheter. Cancer cells take up this dye and are visible under blue light, providing visual clues on areas to biopsied or resected.[39]

Urine cytology can be obtained in voided urine or at the time of the cystoscopy ("bladder washing"). Cytology is not very sensitive for low-grade or grade 1 tumors (a negative result cannot reliably exclude bladder cancer) but has a high specificity (a positive result reliably detects bladder cancer).[40] There are newer non-invasive urine bound markers available as aids in the diagnosis of bladder cancer, including human complement factor H-related protein, high-molecular-weight carcinoembryonic antigen, and nuclear matrix protein 22 (NMP22).[41] NMP22 is also available as a prescription home test. Other non-invasive urine based tests include the CertNDx Bladder Cancer Assay, which combines FGFR3 mutation detection with protein and DNA methylation markers to detect cancers across stage and grade, UroVysion, and Cxbladder.

However, visual detection in any form listed above, is not sufficient for establishing pathological classification, cell type or the stage of the present tumor. A so-called cold cup biopsy during an ordinary cystoscopy (rigid or flexible) will not be sufficient for pathological staging either. Hence, a visual detection needs to be followed by transurethral surgery. The procedure is called transurethral resection of bladder tumor (TURBT). Further, bimanual examination should be carried out before and after the TURBT to assess whether there is a palpable mass or if the tumour is fixed ("tethered") to the pelvic wall. The pathological classification and staging information obtained by the TURBT-procedure, is of fundamental importance for making the appropriate choice of ensuing treatment and/or follow-up routines.[42]

Pathological classificationEdit

 
Histopathology of urothelial carcinoma of the urinary bladder. Transurethral biopsy. H&E stain

95% of bladder cancers are transitional cell carcinoma. The other 5% are squamous cell carcinoma, adenocarcinoma, sarcoma, small cell carcinoma, and secondary deposits from cancers elsewhere in the body.[43] Depending on pattern of growth transitional cell carcinoma can be classified as papillary or non-papillary. Non-papillary carcinoma includes carcinoma in situ (CIS), microinvasive carcinoma and frankly invasive carcinoma.[44]

Transitional cell carcinoma can undergo divergent differentiation (25%) into its variants.[44][45][46] Histologically, papillary transitional cell carcinoma can present in its typical form or with divergent differentiation (squamous, glandular differentiation or micropapillary variant). Divergent histologies of non-papillary transitional cell carcinoma are listed below.

Variant Histology Percentage of cases Implications[47]
Squamous differentiation Presence of intercellular bridges or keratinization 60% Outcomes similar to conventional transitional cell carcinoma
Glandular differentiation Presence of true glandular spaces 10%
Sarcomatoid foci Presence of both epithelial and mesenchymal differentiation 7% Clinically aggressive[48]
Micropapillary variant Resembles papillary serous carcinoma of the ovary or resembling micropapillary carcinoma of breast or lung[49] 3.7% Clinically aggressive, early cystectomy recommended
Urothelial carcinoma with small tubules and microcystic form Presence of cysts with a size range of microscopic to 1-2mm Rare
Lymphoepithelioma-like carcinoma Resembles lymphoepithelioma of the nasopharynx
Lymphoma-like and plasmacytoid variants Malignant cells resemble cells of malignant lymphoma or plasmacytoma
Nested variant Histologically look similar to von Brunn’s nests Can be misdiagnosed as benign von brunn’s nests or non-invasive low-grade papillary urothelial carcinoma
Urothelial carcinoma with giant cells Presence of epithelial tumour giant cells and looks similar to giant cell carcinoma of the lung
Trophoblastic differentiation Presence of syncytiotrophoblastic giant cells or choriocarcinomatous differentiation, may express HCG
Clear cell variant Clear cell pattern with glycogen-rich cytoplasm
Plasmacytoid Cells with abundant lipid content, mimic signet ring cell adenocarcinoma of stomach/ lobular breast cancer Clinically aggressive, propensity for peritoneal spread
Unusual stromal reactions Presence of following; pseudosarcomatous stroma, stromal osseous or cartilaginous metaplasia, osteoclast-type giant cells, lymphoid infiltrate

Carcinoma in situ (CIS) invariably consists of cytologically high-grade tumour cells.[50]

StagingEdit

 
Diagram showing the T stages of bladder cancer
 
Stage N1 bladder cancer
 
Advanced bladder cancer (M1b)

Bladder cancer is staged (classified by the extent of spread of the cancer) and graded (how abnormal and aggressive the cells appear under the microscope) to determine treatments and estimate outcomes. Staging usually follows the first transurethral resection of bladder tumor (TURBT). If invasive or high grade (includes carcinoma in situ) cancer is detected, a CT scan (abdomen and pelvis or urogram) and CT chest or x-ray chest should be conducted for disease staging. Increase in alkaline phosphatase levels without evidence of liver disease should be evaluated for bone metastasis by a bone scan.[51] Papillary tumors confined to the mucosa or which invade the lamina propria are classified as Ta or T1. Flat lesion are classified as Tis. Both are grouped together as non-muscle invasive disease for therapeutic purposes.

In the TNM staging system (8th Edn. 2017) for bladder cancer:[52][53]

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
  • 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)
  • 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 in true pelvis (hypogastric, obturator, external iliac, or presacral nodes)
  • N2 Metastasis in multiple lymph nodes in true pelvis (hypogastric, obturator, external iliac, or presacral nodes)
  • N3 Metastasis in common iliac lymph node(s)

M (Distant metastasis)

  • MX Distant metastasis cannot be assessed
  • M0 No distant metastasis
  • M1 Distant metastasis.
    • M1a: The cancer has spread only to lymph nodes outside of the pelvis.
    • M1b: The cancer has spread other parts of the body.

The most common sites for bladder cancer metastases are the lymph nodes, bones, lung, liver, and peritoneum.[54]

Numerical
The stages above can be integrated into a numerical staging (with Roman numerals) as follows:[55]

Stage Tumor Nodes Metastasis 5-year survival in the US[56]
Stage 0a Ta N0 M0 98%
Stage 0is Tis N0 M0 95%
Stage I T1 N0 M0 63%
Stage II T2a N0 M0
T2b
Stage IIIA T3a N0 M0 35%
T3b
T4a
T1-4a N1
Stage IIIB T1-4a N2 M0
N3
Stage IVA T4b Any N M0
Any T M1a
Stage IVB Any T ny N M1b 5%

GradingEdit

According to WHO classification (1973) bladder cancers are histologically graded into:[57]

  • G1 – Well differentiated,
  • G2 – Moderately differentiated
  • G3 – Poorly differentiated

WHO classification (2004)[58][59]

  • Papillary lesions
    • Urothelial Papilloma
    • Papillary urothelial neoplasm of low malignant potential (PUNLMP)
    • Low Grade
    • High Grade
  • Flat lesions
    • Urothelial proliferation of uncertain malignant potential
    • Reactive atypia
    • Atypia of unknown significance
    • Urothelial dysplasia
    • Urothelial CIS (always high grade)
      • Primary
      • Secondary
      • Concurrent

Risk stratificationEdit

People are risk-stratified based on clinical and pathological factors so that they are treated appropriately depending on their probability of having progression and/or recurrence.[60] People with non-muscle invasive tumors are categorized into low-risk, intermediate-risk and high-risk or provided with a numerical risk score. Risk-stratification framework is provided by American Urology Association/Society of Urological Oncology (AUA/SUO stratification), European Association of Urology (EAU) guidelines, European Organization for Research and Treatment of Cancer (EORTC) risk tables and Club Urológico Español de Tratamiento Oncológico (CUETO) scoring model.[61][62][63]

AUA risk stratification for non-muscle invasive bladder cancer[61]
Low risk Intermediate risk High risk
Low grade solitary Ta tumor, smaller than 3 cm Recurrence within 1 year, Low grade Ta tumor High grade T1
Papillary urothelial neoplasm of low malignant potential Solitary low grade Ta tumor, bigger than 3 cm Any recurrent tumor Or any hight grade Ta
Low grade Ta, multifocal tumors High grade Ta, bigger than 3 cm (or multifocal)
High grade Ta, smaller than 3 cm Any carcinoma in situ
Low grade T1 Any BCG failure in High grade patient
Any variant histology
Any lymphovascular invasion
Any High grade prostatic urethral involvement

The EORTC and CUETO model use a cumulative score obtained from individual prognostic factors, which are then converted into risk of progression and recurrence. The six prognostic factors included in the EORTC model are number of tumors, recurrence rate, T-stage, presence of carcinoma-in-situ and grade of the tumor.Scoring for recurrence in the CUETO model incorporates 6 variables; age, gender, grade, tumor status, number of tumors and presence of tis. For progression scoring the previous 6 variables plus T stage is used.[64][65]

EORTC/CUETO risk of recurrence depending on the cumulative score[66][67]
Model Cumulative score for recurrence Recurrence at 1-year (%) Recurrence at 5-year (%)
EORTC 0 15 31
1-4 24 46
5-9 38 62
10-17 61 78
CUETO 0-4 8.2 21
5-6 12 36
7-9 25 48
10-16 42 68
EORTC/CUETO risk of progression depending on the cumulative score
Model Cumulative score for progression Progression at 1-year (%) Progression at 5-year (%)
EORTC 0 0.2 0.8
2-6 1 6
7-13 5 17
12-23 17 45
CUETO 0-4 1.2 3.7
5-6 3 12
7-9 5.5 21
10-16 14 34

Molecular classificationEdit

There are efforts to classify bladder cancer into different molecular subtypes. The variability of the disease is due to differences in cancer cell related pathways, as well as due to varying components of the tumor microenvironment, such as infiltrating immune cells that affect the prognosis after therapy. This classification is not used as a standard of care, but has generated information on subgroup molecular characteristics that can be used in the future for stratified or personalized therapies.[68]

PreventionEdit

As of 2015, there is limited high level evidence to suggest that eating vegetable and fruits decreases the risk of bladder cancer.[37] A 2008 study concluded that "specific fruit and vegetables may act to reduce the risk of bladder cancer."[69] Fruit and yellow-orange vegetables, particularly carrots and those containing selenium,[70] are probably associated with a moderately reduced risk of bladder cancer. Citrus fruits and cruciferous vegetables were also identified as having a possibly protective effect. However an analysis of 47,909 men in the Health Professionals Follow-Up Study showed little relation between cancer reduction and high consumption of fruits and vegetables overall, or yellow or green leafy vegetables specifically, compared to the reduction seen among those men who consumed large amounts of cruciferous vegetables.

While it is suggested that the polyphenol compounds in tea may have an inhibitory effect on bladder tumor formation and growth, there is limited evidence to suggesting drinking tea decreases bladder cancer risk.[37]

In a 10-year study involving almost 49,000 men, researchers found that men who drank at least 1,44 L of water (around 6 cups) per day had a significantly reduced incidence of bladder cancer when compared with men who drank less. It was also found that: "the risk of bladder cancer decreased by 7% for every 240 mL of fluid added".[71] The authors proposed that bladder cancer might partly be caused by the bladder directly contacting carcinogens that are excreted in urine, although this has not yet been confirmed in other studies.[69]

ScreeningEdit

As of 2019 there is insufficient evidence to determine if screening for bladder cancer in people without symptoms is effective or not.[72]

TreatmentEdit

 
Flow chart of treatment
 
Attenuated strain of M. bovis used in the treatment of bladder cancer

The treatment of bladder cancer depends on how deeply the tumor invades into the bladder wall.

Treatment strategies for bladder cancer include:[73]

  • Non-muscle invasive: transurethral resection of bladder tumor (TURBT) with or without intavesical chemotherapy or immunotherapy
  • Muscle invasive: radical cystectomy plus neoadjuvant chemotherapy (multimodal therapy) or transurethral resection with chemoradiation (trimodal therapy)
  • Metastatic disease: cisplatin-based chemotherapy
  • Metastatic disease with contraindication for chemotherapy: checkpoint inhibitors
  • Squamous cell carcinoma of bladder: radical cystectomy

Non-muscle invasiveEdit

Transurethral resectionEdit

Non-muscle invasive bladder cancer (those not entering the muscle layer of the bladder) can be "shaved off" using an electrocautery device attached to a cystoscope, which in that case is called a resectoscope. The procedure is called transurethral resection of bladder tumor (TURBT) and serves primarily for pathological staging. In case of non-muscle invasive bladder cancer the TURBT is in itself the treatment, but in case of muscle invasive cancer, the procedure is insufficient for final treatment.[42] Additionally, blue light cystoscopy with optical-imaging agent Hexaminolevulinate (HAL) is recommended at initial TURBT to increase lesion detection and improve resection quality thereby reducing recurrence.[74][75] It is important to assess the quality of the resection, if there is evidence of incomplete resection or there is no muscle in the specimen (without which muscle invasiveness cannot be determined) a second TURBT is strongly recommended.[76] At this point classifying people into risk groups is recommended. For low risk tumors the first surveillance cystoscopy should be carried out within 3 to 4 weeks of initial treatment to determine recurrence of cancer.[77] if negative, a second cystoscopy is carried out at 12 months and then yearly for 5-years.[42]

ChemotherapyEdit

A single instillation of chemotherapy into the bladder after primary TURBT has shown benefit in deceasing recurrence. Medications which can used for this purpose are mitomycin C (MMC), epirubicin, pirarubicin and gemcitabine. Instillation of post-operative chemotherapy should be conducted within first few hours after TURBT. As time progress residual tumor cells are known to adhere firmly and are covered by extracellular matrix which decrease the efficacy of the instillation.[76] If there is a suspicion of bladder perforation during TURBT, chemotherapy should not be instilled into the bladder. Studies have shown that efficacy of chemotherapy is increased by the use of  Device assisted chemotherapy .[78] These technologies use different mechanisms to facilitate the absorption and action of a chemotherapy drug instilled directly into the bladder. Another technology – electromotive drug administration (EMDA) – uses an electric current to enhance drug absorption after surgical removal of the tumor.[79][80] Another technology, thermotherapy, uses radio-frequency energy to directly heat the bladder wall, which together with chemotherapy shows a synergistic effect, enhancing each other's capacity to kill tumor cells. This technology has been studied by a number of different investigators.[81][82][83][84]

ImmunotherapyEdit

 
Drug treatment (chemotherapy) into the bladder(Intravesical)

Immunotherapy by Bacillus Calmette–Guérin (BCG) delivery into the bladder is also used to treat and prevent the recurrence of NMIBC.[85] BCG is a vaccine against tuberculosis that is prepared from attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans. BCG immunotherapy is effective in up to 2/3 of the cases at this stage, and in randomized trials has been shown to be superior to standard chemotherapy.[86] The exact mechanism by which BCG prevents recurrence is unknown. However, it has been shown that the bacteria are taken up the cancer cells.[87] The infection of these cells in the bladder may trigger a localized immune reaction which clears residual cancer cells.[88][89]

People whose tumors recurred after treatment with BCG are more difficult to treat.[90] Many physicians recommend cystectomy for these patients. This recommendation is in accordance with the official guidelines of the European Association of Urologists (EAU)[91] and the American Urological Association (AUA)[92]

Treatment after primary TURBT[42]
Risk Other considerations Chemotherapy Immunotherapy (BCG) Cytoscopy
Low - - - at 3-months followed by cystoscopy at 12-months, then yearly for 5-years
Intermediate (primary or recurrent tumors) No previous chemotherapy   Intravesical chemotherapy for 1 year OR Intravesical BCG for 1 year at 3-months followed by once every 3–6 months for 5-years and then yearly.
Previous chemotherapy - Intravesical BCG for 1 year
High - - Intravesical BCG for 3 year (as tolerated) at 3-months with cytology followed by once every 3-months for 2-years after that, 6 monthly for 5 years then yearly.
T1G3/High grade, Lymphovascular invasion, presence of variant histology Consider radical cystectomy

Muscle invasiveEdit

 
Surgical reconstruction (neobladder) of the bladder following removal.

Multimodal therapyEdit

Untreated, superficial tumors may gradually begin to infiltrate the muscular wall of the bladder (muscle invasive bladder cancer). Tumors that infiltrate the bladder wall require more radical surgery, where part (partial cystectomy) or all (radical cystectomy) of the bladder is removed (a cystectomy) and the urinary stream is diverted into an isolated bowel loop (called an ileal conduit or urostomy). In some cases, skilled surgeons can create a substitute bladder (a neobladder) from a segment of intestinal tissue, but this largely depends upon patient preference, age of patient, renal function, and the site of the disease. Even after surgical removal of bladder, 50% of the people with muscle invasive disease (T2-T4) develop metastatic disease within two years due to micrometastasis,.[93] In such, neoadjuvant chemotherapy (chemotherapy before main treatment, ie surgery) has shown to increase overall survival at 5 years from 45% to 50% with a absolute survival benefit of 5%.[94][95][96] Currently the two most used chemotherapy regimens for neoadjuvant chemotherapy are platinum based; methotrexate, vinblastine, doxorubicin, with cisplatin (MVAC) and gemcitabine with cisplatin/carboplatin (GC).[97] Although, optimal regime has not been established, the preferred regime for neoadjuvant therapy is MVAC.[97]

Trimodal therapyEdit

In patients with T2N0M0 tumors, a combination of radiation and chemotherapy in conjunction with transurethral (endoscopic) bladder tumor resection can be used as an alternative.[98] Review of available large data series on this so-called trimodality therapy has indicated similar long-term cancer specific survival rates, with improved overall quality of life as for patients undergoing radical cystectomy with urinary reconstruction. These patients are usually highly selected and do not have multi-focal disease or carcinoma in-situ, which is associated with a higher rate of recurrence, progression, and death from bladder cancer versus patients who undergo radical cystectomy.[99]

For muscle invasive urothelial urinary bladder cancer there are a number of treatment options. The best approach is radical cystectomy, as mentioned. In males, this usually includes also the removal of the prostate; and in females it involves removal of ovaries, uterus and parts of the vagina.

Metastatic diseaseEdit

Cisplatin-containing combination chemotherapy is the standard of care for metastatic bladder care.[100]Again, two most used chemotherapy regimens for chemotherapy in metastatic bladder cancer are platinum based; methotrexate, vinblastine, doxorubicin, with cisplatin (MVAC) and gemcitabine with cisplatin/carboplatin (GC). Paclitaxel can be added with gemcitabine and cisplatin (PCG regimen; triple therapy) as an alternative treatment. MVAC is better tolerated if it is combined with granulocyte colony-stimulating factor. This combination has shown to decease all cause mortality.[101]

Bladder cancer that is refractory or shows progression after platinum based chemotherapy can be treated with Vinflunine, a third generation vinca alkaloid (approved in Europe).[102]

PrognosisEdit

People with superficial tumors, also known as non-muscle invasive tumors, have a favorable outcome (5-year survival is 95% vs. 69% of muscle invasive bladder cancer).[103][104] However, 70% of them will have a recurrence after initial treatment with 30% of them presenting with muscle invasive disease.[105] Recurrence and progression to a higher disease stage have a less favorable outcome.[106]

EpidemiologyEdit

Top countries by new cases of bladder cancer per 100,000 (2018)[107][108]
Rank Country Overall Men Women
1 Lebanon 25 40 9
2 Greece 21 40 4
3 Denmark 18 29 8
4 Hungary 17 27 9
5 Albania 16 27 6
5 Netherlands 16 26 8
7 Belgium 16 27 6
8 Italy 15 27 6
9 Germany 15 26 6
10 Spain 15 27 6
 
Age-standardized death from bladder cancer per 100,000 inhabitants in 2004.[109]
  no data
  less than 1.5
  1.5–3
  3–4.5
  4.5–6
  6–7.5
  7.5–9
  9–10.5
  10.5–12
  12–13.5
  13.5–15
  15–16.5
  more than 16.5

Globally, in 2017, bladder cancer resulted in 196,000 deaths, a 5.4% (age adjusted) decrease from 2007.[110] In 2018, the age adjusted rates of new cases of bladder cancer was 6 cases per 100,000 people and age adjusted death rate was 2 deaths per 100,000 people. Lebanon and Greece have the highest rate of new cases. In Lebanon, this high risk is attributed to high number of smokers and petrochemical air pollution.[111] Risk of bladder cancer occurrence is 4 times higher in men than women.[5] Smoking can only partially explain this higher rates in men in western hemisphere.[112] One other reason is that the androgen receptor, which is much more active in men than in women, may play a part in the development of the cancer.[113] In Africa, men are more prone to do field work and are exposed to infection with Schistosoma, this may explain to a certain extent the gap in incidence.[112] However, women present with more aggressive disease and have worse outcomes than men. This difference in outcomes is attributed to numerous factors such as, difference in carcinogen exposure, genetics, social and quality of care.[114]

CanadaEdit

Bladder cancer is 6th most common cancer accounting for 3.7% of the new cancer cases. In 2018, 9160 new cases were diagnosed and 2467 died from it.[115]

ChinaEdit

Bladder cancer is 14th most common cancer and 16th most common cause of cancer death. In, 2018 it accounted for 82,300 new cases and 38,200 deaths.[116]

UKEdit

Bladder cancer is the ninth most common cancer in the UK accounting for 2.7% of all the new cancers cases. In 2018, there was 12,200 new cases and 6100 people died from it.[117]

USEdit

In the United States in 2019 80,470 cases and 17,670 deaths are expected making it the 6th most common type of cancer in the region.[2] Bladder cancer is the fourth most common type of cancer in men and the ninth most common cancer in women. More than 60,000 men and 16,000 women are diagnosed with bladder cancer each year.

See alsoEdit

ReferencesEdit

  1. ^ a b c d e f g h i j "Bladder Cancer Treatment". National Cancer Institute. 1 January 1980. Archived from the original on 14 July 2017. Retrieved 18 July 2017.
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  10. ^ "Bladder cancer". World Cancer Research Fund. 24 April 2018.
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