Bladder cancer
Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain.
Risk factors for bladder cancer include smoking, family history, prior radiation therapy, frequent bladder infections, and exposure to certain chemicals. The most common type is transitional cell carcinoma. Other types include squamous cell carcinoma and adenocarcinoma. Diagnosis is typically by cystoscopy with tissue biopsies. Staging of the cancer is determined by transurethral resection and medical imaging.
Treatment depends on the stage of the cancer. It may include some combination of surgery, radiation therapy, chemotherapy, or immunotherapy. Surgical options may include transurethral resection, partial or complete removal of the bladder, or urinary diversion. The typical five-year survival rates in the United States is 77%, Canada is 75%, and Europe is 68%.
Bladder cancer, as of 2018, affected about 1.6 million people globally with 549,000 new cases and 200,000 deaths. Age of onset is most often between 65 and 84 years of age. Males are more often affected than females. 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. The highest rates of bladder cancer deaths were seen in Northern Africa and Western Asia followed by Southern Europe.
Signs and symptoms
Bladder cancer characteristically causes blood in the urine, which may be visible or detectable only by microscope. 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. 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 would typically be painful.Other possible symptoms include pain during urination, 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. Some rare forms of bladder cancer like urachal adenocarcinoma produce mucin, which is then excreted in the urine causing it to be thick.
People with advanced disease may have pelvic or bony pain, lower-extremity swelling, or flank pain. Rarely, a palpable mass can be detected on physical examination.
Causes
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, however these proportions have reduced over recent years since there are fewer smokers in Europe and North America. There is an almost linear relationship between smoking duration, pack years and bladder cancer risk. A risk plateau at smoking about 15 cigarettes a day can be observed. Smoking in any form increases the risk for bladder cancer. Quitting smoking reduces the risk. Risk of bladder cancer decreases by 30% within 1–4 years and continues to decrease by 60% at 25 years after smoking cessation. However, former smokers will most likely always be at a higher risk of bladder cancer compared to people who have never smoked. Passive smoking also appear to be a risk.Opium consumption increases the risk of bladder cancer by 3-fold and concurrent use of opium and smoking increases the risk of bladder cancer by 5 times compared to the general population.
Thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens. Occupational or circumstantial exposure to the following substances has been implicated as a cause of bladder cancer; benzidine, 4-aminobiphenyl, 2-naphtylamine, phenacetin, arsenic and chlorinated aliphatic hydrocarbons in drinking water, auramine, magenta, ortho-toluidine, epoxy and polyurethane resin hardening agents, chlornaphazine, coal-tar pitch. Occupations at risk are bus drivers, rubber workers, painters, motor mechanics, leather workers, blacksmiths, machine setters, and mechanics. Hairdressers are thought to be at risk as well because of their frequent exposure to permanent hair dyes.
Infection with Schistosoma haematobium may cause bladder cancer, specially of the squamous cell type. Schistosoma eggs induces a chronic inflammatory state in the bladder wall resulting in tissue fibrosis. Higher levels of N-nitroso compounds has been detected in urine samples of people with schistosomiasis. N-Nitroso compounds have been implicated in the pathogenesis of schistosomiasis related bladder cancer. They cause alkylation DNA damage, specially Guanine to Adenine transition mutations in the HRAS and p53 tumor suppressor gene. 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%. Other causes of squamous cell carcinoma of the bladder include chronic catheterizations in people with a spinal cord injury and history of treatment with cyclophosphamide.
Ingestion of aristolochic acid present in many Chinese herbal medications has been shown to cause urothelial carcinoma and kidney failure. Aristolochic acid activates peroxidase in the urothelium and causes transversion mutation in the TP53 tumor suppressor gene.
People who undergo external beam radiotherapy for prostate cancer have a higher risk of developing invasive bladder cancer.
In addition to these major risk factors there are also numerous other modifiable factors that are less strongly associated with bladder cancer, for example, obesity. 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.
Genetics
Mutations in FGFR3, TP53, PIK3CA, KDM6A, ARID1A, KMT2D, HRAS, TERT, KRAS, CREBBP, RB1 and TSC1 genes may be associated with some cases of bladder cancer. Deletions of parts or whole of chromosome 9 is common in bladder cancer. Low grade cancer are known to harbor mutations in RAS pathway and the fibroblast growth factor receptor 3 gene, both of which play a role in the MAPK/ERK pathway. p53 and RB gene mutations are implicated in high-grade muscle invasive tumors. Eighty nine percent of muscle invasive cancers have mutations in chromatin remodeling and histone modifying genes.Deletion of both copies of the GSTM1 gene has a modest increase in risk of bladder cancer. GSTM1 gene product glutathione S-transferase M1 participates in the detoxification process of carcinogens such as polycyclic aromatic hydrocarbons found in cigarette smoke. Similarly, mutations in NAT2 is associated with increased risk for bladder cancer. N-acetyltransferase helps in detoxification of carcinogens like aromatic amines. Various single-nucleotide polymorphisms in PSCA gene present on chromosome 8 have shown to increase the risk for bladder cancer. PSCA gene promotor region has an androgen response region. Loss of reactivity of this region to androgens is hypothesized as a cause of more number of aggressive tumors in women.
Muscle invasive bladder cancer are heterogeneous in nature. In general, they can be genetically classified into basal and luminal subtypes. Basal subtype show alterations involving RB and NFE2L2 and luminal type show changes in FGFR3 and KDM6A genes. Basal subtype are subdivided into basal and claudin low-type group and are aggressive and show metastasis at presentation, however they respond to platinum based chemotherapy. Luminal subtype can be subdivided into p53-like and luminal. p53-like tumors of luminal subtype although not as aggressive as basal type, show resistance to chemotherapy
Diagnosis
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 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. Photodynamic detection 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.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 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. Further, a rectal and vaginal 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 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.
If invasive or high grade cancer is detected on TURBT, an MRI and/or CT scan of the abdomen and pelvis or urogram and CT chest or x-ray chest should be conducted for disease staging and to look for cancer spread. Increase in alkaline phosphatase levels without evidence of liver disease should be evaluated for bone metastasis by a bone scan. Although 18F-fluorodeoxyglucose -positron emission tomography /CT has been explored as a viable method for staging, there is no consensus to support its role in routine clinical evaluations.
Urine cytology can be obtained in voided urine or at the time of the cystoscopy. Cytology is not very sensitive for low-grade or grade 1 tumors but has a high specificity. 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. In United States the FDA has approved NMP22, NMP22 BladderChek, and UroVysion tests for detection and surveillance of bladder cancer and ImmunoCyt, BTA-TRAK, and BTA-STAT tests have been approved for surveillance only. BTA-STAT and BladderChek can be performed in the clinic and others are done in the laboratory. Other non-invasive urine based tests include the CertNDx Bladder Cancer Assay, which detects FGFR3 mutation and Urine Bladder Cancer test, which is a sandwich ELISA for Cytokeratin 8/18 fragment. Likewise, NMP22 is a sandwich ELISA and NMP22 BladderChek is a dipstick immunoassay, both of them detect nuclear mitotic apparatus protein tumor marker. UroVysion is a fluorescence in situ hybridization which detects aneuploidy in chromosomes 3, 7, 17 and loss of the 9p21 locus. ImmunoCyt is an Immunofluorescence test which detects glycosylated CEA and MUCIN-like antigens. BTA-STAT is a dipstick immunoassay for detection of human complement factor H-related protein. BTA-TRAK is a sandwich ELISA which also detects human complement factor H-related protein. Sensitivities across biomarkers ranged from 0.57 to 0.82 and specificities from 0.74 to 0.88. Biomarkers fared better when used in combination with urine cytology than when used alone. However, detection accuracy is poor for low grade cancers and 10% cancers are still missed. Current guidelines do not recommended using urinary biomarkers for detection and surveillance.
Classification
| Type | Relative incidence | Subtypes |
| Transitional cell carcinoma | 95% | Papillary |
| Transitional cell carcinoma | 95% | Non-papillary |
| Non-transitional cell carcinoma | 5% | Squamous cell carcinomas, adenocarcinomas, sarcomas, small cell carcinomas, and secondary deposits from cancers elsewhere in the body. |
Non-papillary carcinoma includes carcinoma in situ, microinvasive carcinoma and frankly invasive carcinoma. Carcinoma in situ invariably consists of cytologically high-grade tumour cells.
Transitional cell carcinoma can undergo differentiation into its variants. When seen under a microscope, papillary transitional cell carcinoma can present in its typical form or as one of its variations. Different variations of non-papillary transitional cell carcinoma are listed below.
| Variant | Histology | Percentage of non-papillary cases | Implications |
| Squamous differentiation | Presence of intercellular bridges or keratinization | 60% | Outcomes similar to conventional transitional cell carcinoma |
| Glandular differentiation | Presence of true glandular spaces | 10% | Outcomes similar to conventional transitional cell carcinoma |
| Sarcomatoid foci | Presence of both epithelial and mesenchymal differentiation | 7% | Clinically aggressive |
| Micropapillary variant | Resembles papillary serous carcinoma of the ovary or resembling micropapillary carcinoma of breast or lung | 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 | Rare | |
| Lymphoma-like and plasmacytoid variants | Malignant cells resemble cells of malignant lymphoma or plasmacytoma | Rare | |
| Nested variant | Histologically look similar to von Brunn's nests | Rare | 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 | Rare | |
| Trophoblastic differentiation | Presence of syncytiotrophoblastic giant cells or choriocarcinomatous differentiation, may express HCG | Rare | |
| Clear cell variant | Clear cell pattern with glycogen-rich cytoplasm | Rare | |
| Plasmacytoid | Cells with abundant lipid content, mimic signet ring cell adenocarcinoma of stomach/ lobular breast cancer | Rare | 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 | Rare |
Staging
Bladder cancer is staged and graded to determine treatments and estimate outcomes. Staging usually follows the first transurethral resection of bladder tumor. 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 for bladder cancer:
T
- TX Primary tumour cannot be assessed
- T0 No evidence of primary tumour
- Ta Non-invasive papillary carcinoma
- Tis Carcinoma in situ
- T1 Tumour invades subepithelial connective tissue
- T2a Tumour invades superficial muscle
- T2b Tumour invades deep muscle
- T3 Tumour invades perivesical tissue:
- * T3a Microscopically
- * T3b Macroscopically
- T4a Tumour invades prostate, uterus or vagina
- T4b Tumour invades pelvic wall or abdominal wall
- NX Regional lymph nodes cannot be assessed
- N0 No regional lymph node metastasis
- N1 Metastasis in a single lymph node in true pelvis
- N2 Metastasis in multiple lymph nodes in true pelvis
- N3 Metastasis in common iliac lymph nodes
- 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.
Numerical
The stages above can be integrated into a numerical staging as follows:
| Stage | Tumor | Nodes | Metastasis | 5-year survival in the US |
| Stage 0a | Ta | N0 | M0 | 98% |
| Stage 0is | Tis | N0 | M0 | 95% |
| Stage I | T1 | N0 | M0 | 63% |
| Stage II | T2a | N0 | M0 | 63% |
| Stage II | T2b | N0 | M0 | 63% |
| Stage IIIA | T3a | N0 | M0 | 35% |
| Stage IIIA | T3b | N0 | M0 | 35% |
| Stage IIIA | T4a | N0 | M0 | 35% |
| Stage IIIA | T1-4a | N1 | M0 | 35% |
| Stage IIIB | T1-4a | N2 | M0 | 35% |
| Stage IIIB | T1-4a | N3 | M0 | 35% |
| Stage IVA | T4b | Any N | M0 | 35% |
| Stage IVA | Any T | Any N | M1a | 35% |
| Stage IVB | Any T | ny N | M1b | 5% |
Grading
According to WHO classification bladder cancers are histologically graded into:- G1 – Well differentiated,
- G2 – Moderately differentiated
- G3 – Poorly differentiated
- Papillary lesions
- *Urothelial Papilloma
- *Papillary urothelial neoplasm of low malignant potential
- *Low Grade
- *High Grade
- Flat lesions
- *Urothelial proliferation of uncertain malignant potential
- *Reactive atypia
- *Atypia of unknown significance
- *Urothelial dysplasia
- *Urothelial CIS
- **Primary
- **Secondary
- **Concurrent
Risk stratification
| 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 | |
| High grade Ta, smaller than 3 cm | Any carcinoma in situ | |
| Low grade T1 | Any BCG failure in high grade tumors | |
| 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.
| Model | Cumulative score for recurrence | Recurrence at 1-year | Recurrence at 5-year |
| EORTC | 0 | 15 | 31 |
| EORTC | 1-4 | 24 | 46 |
| EORTC | 5-9 | 38 | 62 |
| EORTC | 10-17 | 61 | 78 |
| CUETO | 0-4 | 8.2 | 21 |
| CUETO | 5-6 | 12 | 36 |
| CUETO | 7-9 | 25 | 48 |
| CUETO | 10-16 | 42 | 68 |
Prevention
As of 2019, there is limited high level evidence to suggest that eating vegetable and fruits decreases the risk of bladder cancer. A 2008 study concluded that "specific fruit and vegetables may act to reduce the risk of bladder cancer." Fruit and yellow-orange vegetables, particularly carrots and those containing selenium, 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. An inverse relation between in-takes of flavonols and lignans and aggressive bladder cancer has also been described.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.
In a 10-year study involving almost 49,000 men, researchers found that men who drank at least 1.44 L of water per day had a reduced risk 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". 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.
Screening
As of 2019 there is insufficient evidence to determine if screening for bladder cancer in people without symptoms is effective or not.Treatment
The treatment of bladder cancer depends on how deeply the tumor invades into the bladder wall.Treatment strategies for bladder cancer include:
- Non-muscle invasive: transurethral resection of bladder tumor with or without intavesical chemotherapy or immunotherapy
- Muscle invasive
- *Stage II/Stage IIIA: radical cystectomy plus neoadjuvant chemotherapy or transurethral resection with chemoradiation or partial cystectomy plus neoadjuvant chemotherapy
- * Stage IIIB/IVA: cisplatin-based chemotherapy followed by radical cystectomy or chemoradiation or observation depending on treatment response
- *Stage IVB : palliative radiotherapy
- Metastatic disease: cisplatin-based chemotherapy
- Metastatic disease but unfit for cisplatin-based chemotherapy: carboplatin-based chemotherapy
- Metastatic disease with contraindication for chemotherapy: checkpoint inhibitors if programmed death ligand 1 positive
- Squamous cell carcinoma or adenocarcinoma of bladder: radical cystectomy
Non-muscle invasive
Transurethral resection
Non-muscle invasive bladder cancer 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 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. Additionally, blue light cystoscopy with optical-imaging agent Hexaminolevulinate is recommended at initial TURBT to increase lesion detection and improve resection quality thereby reducing recurrence. 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 a second TURBT is strongly recommended. Moreover, nearly half of the people with high grade non-invasive disease have residual tumor after primary TURBT, in such cases a second TURBT is important for avoiding under-staging. At this point classifying people into risk groups is recommended. Treatment and surveillance for different risk groups is indicated in the table below.Chemotherapy
A single instillation of chemotherapy into the bladder after primary TURBT has shown benefit in deceasing recurrence by 35% in non-muscle invasive disease. Medications which can used for this purpose are mitomycin C, 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. The most common side effect is chemical cystitis and skin irritation. If there is a suspicion of bladder perforation during TURBT, chemotherapy should not be instilled into the bladder as serious adverse events are known to occur due to drug extravasation. Studies have shown that efficacy of chemotherapy is increased by the use of Device assisted chemotherapy. 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 – uses an electric current to enhance drug absorption after surgical removal of the tumor. 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.Immunotherapy
by Bacillus Calmette–Guérin delivery into the bladder is also used to treat and prevent the recurrence of NMIBC. BCG is a vaccine against tuberculosis that is prepared from attenuated 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. The exact mechanism by which BCG prevents recurrence is unknown. However, it has been shown that the bacteria are taken up the cancer cells. The infection of these cells in the bladder may trigger a localized immune reaction which clears residual cancer cells.BCG is delivered as induction and a maintenance course. The induction course consists of 6-week course of intravesical and percutaneous BCG. This is followed by a maintenance course. There is no consensus regarding the maintenance schedule, however the most commonly followed is the Southwestern Oncology Group schedule. The SWOG maintenance schedule consists of intravesical and percutaneous BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months. Three weekly maintenance regimen with induction has shown complete response rate of 84% compared to 69% in people who received 6 week induction BCG only at 6 months. Many studies have explored alternate treatment schedules and regimes of BCG but has shown no clinical significance. Efficacy of different strains of BCG has been shown not to be different however, there is no high-level evidence.
Side effects of BCG therapy include cystitis, prostatitis, epididymo-orchitis, balanitis, ureteral obstruction, bladder contraction, mycobacterial osteomyelitis, reactive arthritis, mycobacterial pneumonia, granulomatous hepatitis, , interstitial nephritis, infectious vasculitis and disseminated infection.
Local infection because of BCG should be treated with triple tubercular therapy, with one of the drug being fluoroquinolone for 3 to 6 months. In people with systemic infections, BCG therapy should be stopped and anti-tubercular multidrug treatment for at-least 6 months should be started. Medications that can be used for this treatment are INH, rifampicin, ethambutol, fluoroquinolones, clarithromycin, aminoglycosides, and doxycycline. BCG strains are not sensitive to pyrazinamide therefore, it should not be a part of anti-tubercular treatment.
BCG treatment failure
BCG treatment failure can be classified into 3 groups; BCG relapse, BCG-refractory and BCG-intolerant. In BCG relapse, tumor reoccurs after a disease free period. BCG-refractory tumors are the ones which does not respond to induction and maintenance doses of BCG or which progress during therapy. In BCG-intolerant, tumor reoccurs due to incomplete treatment as the person receiving it is unable to tolerate induction course of BCG. Around 50% of the people fail BCG treatment and would require further treatment.People whose tumors recurred after treatment with BCG or unresponsive to treatment are more difficult to treat. In such people a radical cystectomy is recommendation In people who do not show response to BCG therapy and are unfit or unwilling to undergo radical cystectomy, salvage therapies can considered. Salvage therapy include intravesical chemotherapy with agents such as valrubicin, gemcitabine or docetaxel, chemoradiation or chemohyperthermia.
| Risk | Other considerations | Chemotherapy | Immunotherapy | Cystoscopy | Imaging |
| Low | at 3-months followed by cystoscopy at 12-months, then yearly for 5-years | CT/MR urography and CT/MRI of abdomen and pelvis at baseline | |||
| Intermediate | Primary tumor with history of chemotherapy | Intravesical chemotherapy for 1 year OR Intravesical BCG for 1 year | Intravesical chemotherapy for 1 year OR Intravesical BCG for 1 year | at 3-months with cytology followed by once every 3–6 months for 5-years and then yearly | CT/MR urography and CT/MRI of abdomen and pelvis at baseline |
| Intermediate | Recurrent tumors with history of previous chemotherapy | Intravesical BCG for 1 year | at 3-months with cytology followed by once every 3–6 months for 5-years and then yearly | CT/MR urography and CT/MRI of abdomen and pelvis at baseline | |
| High | Intravesical BCG for 3 year | at 3-months with cytology followed by once every 3-months for 2-years after that, 6 monthly for 5 years then yearly | CT/MR urography and CT/MRI of abdomen and pelvis at baseline, CT/MR urography 1-2 yearly for 10 years | ||
| High | T1G3/High grade, Lymphovascular invasion, Presence of variant histology | Consider radical cystectomy | Consider radical cystectomy | Consider radical cystectomy | CT/MR urography and CT/MRI of abdomen and pelvis at baseline, CT/MR urography 1-2 yearly for 10 years |
Muscle invasive
Multimodal therapy (standard treatment)
Untreated, non-muscle invasive tumors may gradually begin to infiltrate the muscular wall of the bladder. Tumors that infiltrate the bladder wall require more radical surgery, where part or all of the bladder is removed and the urinary stream is diverted into an isolated bowel loop. In some cases, skilled surgeons can create a substitute bladder from a segment of intestinal tissue, but this largely depends upon a person's preference, age of the person, renal function, and the site of the disease. A bilateral pelvic lymphadenectomy should accompany radical cystectomy. At minimum, a standard template of lymphadenectomy should be followed by removing the external and internal iliac and . Radical cystectomy has a significant morbidity associated with it. About 50-65% of the people experience complication within 90 days of surgery. Mortality rates was 7% within 90 days of surgery. High volume centers have better outcomes than low volume centers. Some centers are implementing Enhanced Recovery After Surgery society recommendations to decrease morbidity after radical cystectomy. However, due to lack of specific evidence in urologic surgery, ERAS protocol has not been widely incorporated in urologic clinical care.Even after surgical removal of bladder, 50% of the people with muscle invasive disease develop metastatic disease within two years due to micrometastasis,. In such, neoadjuvant chemotherapy has shown to increase overall survival at 5 years from 45% to 50% with an absolute survival benefit of 5%. Currently the two most used chemotherapy regimens for neoadjuvant chemotherapy are platinum based; methotrexate, vinblastine, doxorubicin, cisplatin and gemcitabine with cisplatin. Other regimens include dose dense MVAC and cisplatin, methotrexate and vinblastine.
Although, the optimal regimen has not been established, the preferred regimen for neoadjuvant therapy is MVAC.
Role of adjuvant chemotherapy is limited to people with high grade tumours and who have not been treated with neoadjuvant therapy. Adjuvant radiation therapy has not shown any advantage in bladder cancer treatment.
| MVAC | DDMVAC | Gemcitabine + cisplatin |
| Methotrexate - day 1,15,22 Vinblastine - day 2, 15, 22 Doxorubicin - day 2 Cisplatin - day 2 Repeat every 4 weeks for 3 cycles | Methotrexate - day 1 Vinblastine - day 2 Doxorubicin - day 2 Cisplatin - day 2 Granulocyte colony-stimulating factor - day 4-10 Repeat every 2 weeks for 3–4 cycles | Gemcitabine - day 1,8,15 Cisplatin - day 2 Repeat every 4 weeks for 4 cycles |
Trimodal therapy (alternative treatment)
A combination of radiation and chemotherapy in conjunction with transurethral bladder tumor resection can be used as an alternative in certain people. 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 people undergoing radical cystectomy with urinary reconstruction. However, currently no randomized control trials are available which has compared trimodal therapy with radical cystectomy. People who undergo trimodal therapy are usually highly selected and generally have T2 disease without hydronephrosis and/or carcinoma in-situ. Five year cancer specific survival and overall survival after trimodal therapy is between 50% to 82% and 36% to 74%.In trimodal therapy, a maximal TURBT is conducted followed by chemoradiation therapy. Radiation sensitizing chemotherapy regimens consisting of cisplatin or 5-flurouracil and mitomycin C are used. Radiation therapy is via external bean radiotherapy with a target curative dose of 64-66 Gy. Surveillance for progression or recurrence should conducted with the aid of CT scans, cystoscopies and urine cytology. Side effects of chemoradiation include nausea, vomiting, loss of appetite, hair loss, mouth sores, diarrhea, constipation, increased risk of infections and bleeding and fatigue.
In people who fail trimodal therapy, radical cystectomy is considered if there is muscle invasive or recurrent tumors. Around 25-30% fail treatment and undergo salvage radical cystectomy. TURBT with intravesical therapy is indicated after treatment failure for non-muscle invasive disease.
Partial cystectomy
In people with solitary tumor without concurrent carcinoma in situ in an area where a clean surgical margins can be achieved, a partial cystectomy with lymphadenectomy can be considered. Management plan including partial cystectomy should be accompanied with neoadjuvant chemotherapy. In people with urachal adenocarcinoma of the bladder, a partial cystectomy with en-bloc resection of urachal ligament and umbilicus can be considered.Metastatic disease
First line treatment
-containing combination chemotherapy is the standard of care for metastatic bladder care. Fitness for receiving cisplatin based chemotherapy is assessed before treatment. A person is deemed unfit if anyone of the following is true.- Eastern Cooperative Oncology Group performance status of 2
- Creatinine clearance < 60 mL/min
- Grade ≥ 2 hearing loss
- Grade ≥ 2 neuropathy
- New York Heart Association Class III heart failure
People with bone metastasis should receive bisphosphonates or denosumab to prevent skeletal related events.
| DDMVAC | Gemcitabine + Cisplatin |
| Methotrexate - day 1 Vinblastine - day 2 Doxorubicin - day 2 Cisplatin - day 2 Granulocyte colony-stimulating factor - day 4-10 Repeat every 2 weeks for 3–4 cycles | Gemcitabine - day 1,8,15 Cisplatin - day 2 Repeat every 4 weeks for 4 cycles |
| Atezolizumab | Gemcitabine + Carboplatin | Pembrolizumab |
| Atezolizumab every 3 weeks | Gemcitabine - day 1,8 Carboplatin - day 1 and every 3 weeks | Pembrolizumab 200 mg every 3 weeks |
Second line treatment
Bladder cancer that is refractory or shows progression after platinum based chemotherapy can be treated with second-line chemotherapy or immunotherapy.The most commonly used second-line chemotherapy is single-agent regimes of Taxanes. Other single-agent regimes include Vinflunine, a third generation vinca alkaloid, Gemcitabine, Pemetrexed, Oxaliplatin, and Ifosfamide. Side effects of Vinflunine include neutropenia, constipation, fatigue and anemia and has limited its use as a second line agent. Response to second-line chemotherapy occurs in 5%–20% people. Median progression free survival with second-line chemotherapy is 3–4 months.
In people with fibroblast growth factor receptors mutations and fail standard platinum based chemotherapy erdafitinib can be used. Erdafitinib has shown a response rate of 40% in these patients. Five immunotherapy agents has been approved in the US for use in metastatic bladder cancer. They act by inhibiting programmed cell-death protein 1 or programmed cell-death ligand 1. Pembrolizumab and nivolumab, and are inhibitors of programmed cell-death ligand 1. Avelumab, atezolizumab and durvalumab are inhibitors of PD-L1.
| Atezolizumab | Nivolumab | Pembrolizumab | Durvalumab | Avelumab |
| Atezolizumab 1200 mg IV every 3 weeks | Nivolumab 3 mg/kg IV every 2 weeks | Pembrolizumab 200 mg every 3 weeks | Durvalumab 10 mg/kg every 2 weeks for 12 months | Avelumab 10 mg/kg IV every 2 weeks |
Surveillance and response
Contrast enhanced CT is used to monitor lung, liver, and lymph node metastasis. A bone scan is used to detect and monitor bone metastasis. Treatment response is measured using the Response evaluation criteria in solid tumors into one of the following groups; response, stable disease and progressive disease.Prognosis
People with non-muscle invasive tumors, have a favorable outcome. However, 70% of them will have a recurrence after initial treatment with 30% of them presenting with muscle invasive disease. Recurrence and progression to a higher disease stage have a less favorable outcome.Survival after radical cystectomy and pelvic lymph node dissection is dependent on the pathological stage. If the disease has not spread to the lymph node and is limited to the bladder the 5-year survival is 78%. If it has spread locally around the region of the bladder with no lymph node involved then the 5-year survival drops to 47%. In disease with lymph node spread the 5-year survival is 31%. Locally advanced and metastatic disease drastically decreases survival, with a median survival of 3–6 months without chemotherapy. Cisplatin-based chemotherapy has increased the median survival to 15-months. However, the 5-year survival is still 15%.
There are several prognostic factors which determine cancer specific survival after radical cystectomy. Factor with detrimental effect of cancer specific survival are old age, higher tumor grade and pathological stage, lymph node metastasis, presence of lymphovascular invasion and positive soft tissue margin. Lymph node density is a predictor of survival in lymph node positive disease. Higher the density lower is the survival.
Quality of life
After radical cystectomy, urinary and sexual function remain inferior to the general population. People who have a neobladder have better emotional function and body image compared with ones with cutaneous diversion. Social factors such family, relationships, health and finances contribute significantly for determining good quality of life in people who have been diagnosed with bladder cancer.A high percentage of people with bladder cancer have anxiety and depression. People who are young, single and have advanced clinical disease have a high risk for getting diagnosed with a psychiatric illness post-treatment. People who suffer from psychiatric illness post treatment seem to have worse cancer specific and overall survival.
Epidemiology
Globally, in 2017, bladder cancer resulted in 196,000 deaths, a 5.4% decrease from 2007. 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.The risk of bladder cancer occurrence is four times higher in men than in women. Smoking can only partially explain this higher rates in men in western hemisphere. 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. This hypothesis is also supported by the fact that men undergoing androgen suppression therapy for unrelated reason seem to have a lower risk of developing bladder cancer. 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 of squamous cell cancers in areas where bladder cancer is endemic. 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. One of the common signs of bladder cancer is hematuria and is quite often misdiagnosed as urinary tract infection in women, leading to a delay in diagnosis. Moreover, as mentioned earlier PSCA gene may play a role in aggressive tumors in women.