Flow chart of 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 (TURBT) with or without intravesical chemotherapy or immunotherapy * Muscle invasive * Stage II/Stage IIIA: radical cystectomy plus neoadjuvant chemotherapy (multimodal therapy, preferred) or transurethral resection with chemoradiation (trimodal therapy, highly selected people) or partial cystectomy plus neoadjuvant chemotherapy (in highly selected people) * Stage IIIB/IVA: cisplatin-based chemotherapy followed by radical cystectomy or chemoradiation or observation depending on treatment response * Stage IVB (locally advanced; unresectable tumors): 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 (PD L1) positive * Squamous cell carcinoma or adenocarcinoma of bladder: radical cystectomy Non-muscle invasive Transurethral resection 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. Additionally, blue light cystoscopy with optical-imaging agent Hexaminolevulinate (HAL) is recommended at initial TURBT to increase lesion detection (especially carcinoma in situ) 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 if there is no muscle in the specimen (without which muscle invasiveness cannot be determined), then a second TURBT is strongly recommended. Moreover, nearly half of the people with high-grade noninvasive 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. Another method for reducing recurrence of tumors is medication after TURBT surgery. The two most common medicines used for this purpose are Bacillus Calmette–Guérin (BCG) and mitomycin. For people who have already had a TURBT procedure, BCG may lead to similar risk of death and may reduce the risk of tumor recurrence. However, this medication may increase the risk of serious unwanted side effects. More research is needed to confirm these results. Chemotherapy Drug treatment (chemotherapy) into the bladder(Intravesical) 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 (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. 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 (EMDA) – 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 (chemohyperthermia) shows a synergistic effect, enhancing each other's capacity to kill tumor cells. Immunotherapy Attenuated strain of M. bovis used in the treatment of bladder cancer Immunotherapy by Bacillus Calmette–Guérin (BCG) 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 (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. The exact mechanism by which BCG prevents recurrence is unknown. However, it has been shown that the bacteria are taken up by 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 (SWOG) 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 (Connaught, TICE, Pasteur, Tokio-172) 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, granulomatous nephritis, interstitial nephritis, infectious vasculitis and disseminated infection. Local infection (i.e. prostatitis, epididymo-orchitis, balanitis) 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 do 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 an 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 who were 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 be considered. Salvage therapy include intravesical chemotherapy with agents such as valrubicin, gemcitabine or docetaxel, chemoradiation or chemohyperthermia. + Treatment and follow-up after primary TURBT Risk Other considerations Chemotherapy Immunotherapy (BCG) Cystoscopy (surveillance) Imaging (surveillance) 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 (preferred) 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 Recurrent tumors with history of 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 CT/MR urography and CT/MRI of abdomen and pelvis at baseline, CT/MR urography 1-2 yearly for 10 years T1G3/High grade, Lymphovascular invasion, Presence of variant histology Consider radical cystectomy Muscle invasive Surgical reconstruction (neobladder) of the bladder following removal. Multimodal therapy (standard treatment) Untreated, non-muscle invasive 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 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 obturator lymph node. When performing a lymphadenectomy, the surgeon can either remove lymph nodes from a smaller (standard) or from larger (extended) area. In comparison with a standard lymph node dissection, having an extended dissection may reduce a person’s likelihood of death from any reason, including dying from
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