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 riskother considerationschemotherapyimmunotherapy (bcg)cystoscopy (surveillance)imaging (surveillance) lowat 3-months followed by cystoscopy at 12-months, then yearly for 5-yearsct/mr urography and ct/mri of abdomen and pelvis at baseline intermediateprimary 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 yearlyct/mr urography and ct/mri of abdomen and pelvis at baseline recurrent tumors with history of previous chemotherapyintravesical bcg for 1 year highintravesical 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 yearlyct/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 histologyconsider radical cystectomy muscle invasive surgical reconstruction (neobladder) of the bladder following removal. multimodal therapy (standard treatment) further information: cystectomy 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 bladder cancer. the extended procedure may lead to more serious unwanted effects and may or may not influence the likelihood of the cancer recurring over time. the rate of not-so-serious side effects may be similar for both surgeries. 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 (eras) 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 (t2-t4) develop metastatic disease within two years due to micrometastasis. in such, neoadjuvant chemotherapy (chemotherapy before main treatment, i.e. surgery) 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 (mvac) and gemcitabine with cisplatin (gc). other regimens include dose dense mvac (ddmvc) and cisplatin, methotrexate and vinblastine (cmv). although, the optimal regimen has not been established, the preferred regimen for neoadjuvant therapy is mvac. role of adjuvant chemotherapy (chemotherapy after main treatment) is limited to people with high grade tumours (pt3/t4and/or n+) and who have not been treated with neoadjuvant therapy. adjuvant radiation therapy has not shown any advantage in bladder cancer treatment. dosage and schedule of chemotherapy regimens for neoadjuvant and adjuvant chemotherapy mvacddmvacgemcitabine + cisplatin methotrexate (30 mg/m2 iv) - day 1,15,22 vinblastine (3 mg/m2 iv) - day 2, 15, 22 doxorubicin (30 mg/m2 iv) - day 2 cisplatin (70 mg/m2 iv) - day 2 repeat every 4 weeks for 3 cycles methotrexate (30 mg/m2 iv) - day 1 vinblastine (3 mg/m2 iv) - day 2 doxorubicin (30 mg/m2 iv) - day 2 cisplatin (70 mg/m2 iv) - day 2 granulocyte colony-stimulating factor (g-csf) (240μg/m2 sc) - day 4-10 repeat every 2 weeks for 3–4 cycles gemcitabine (1,000 mg/m2 iv) - day 1,8,15 cisplatin (70 mg/m2) - day 2 repeat every 4 weeks for 4 cycles trimodal therapy (alternative treatment) a combination of radiation and chemotherapy (chemoradiation) in conjunction with transurethral (endoscopic) 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 (ebrt) 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. first line treatment cisplatin-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 who are deemed fit receive platinum based regimens; methotrexate, vinblastine, doxorubicin, with cisplatin (mvac) or gemcitabine with cisplatin (gc). alternative regimens include paclitaxel with gemcitabine and cisplatin (pcg, triple therapy) and cisplatin, methotrexate and vinblastine (cmv). response rate for cisplatin-based combination ranges from 39 to 65% and complete response is seen in 12-35% of the people. mvac is better tolerated if it is combined with granulocyte colony-stimulating factor and the regimen is known as dose dense mvac regimen (ddmvac). this combination has shown to decease all cause mortality. mvac regimen is aggressive. febrile neutropenia (fever due to decrease in white blood cells) occurs in 10 to 14% and death due to toxicity in about 3-4%. common side effects of mvac include suppression of bone marrow, fever due to decrease in white blood cells, sepsis, mucositis, and nausea and vomiting. in contrast, the gc regimen has shown lower rates of neutropenic sepsis and grade 3/4 mucositis compared to mvac. efforts have been made to increase tolerance of cisplatin-based regimen by replacing it with carboplatin-based chemotherapy. however, cisplatin-based therapy is superior to carboplatin-based chemotherapy in achieving overall and complete response. nevertheless, nearly half of the people with metastatic disease are "unfit" for cisplatin-based therapy. in such persons a combination of carboplatin and gemcitabine (gemcarbo) can be used as first line chemotherapy. in people who are not eligible for any platinum based chemotherapy and have pd-l1 expression, atezolizumab and pembrolizumab can be used. people with bone metastasis should receive bisphosphonates or denosumab to prevent skeletal related events (e.g. fractures, spinal cord compression, bone pain). dosage and schedule of first-line chemotherapy regimens for metastatic bladder cancer in cisplatin eligible people ddmvacgemcitabine + cisplatin methotrexate (30 mg/m2 iv) - day 1 vinblastine (3 mg/m2 iv) - day 2 doxorubicin (30 mg/m2 iv) - day 2 cisplatin (70 mg/m2 iv) - day 2 granulocyte colony-stimulating factor (g-csf) (240μg/m2 sc) - day 4-10 repeat every 2 weeks for 3–4 cycles gemcitabine (1,000 mg/m2 iv) - day 1,8,15 cisplatin (70 mg/m2) - day 2 repeat every 4 weeks for 4 cycles dosage and schedule of first-line chemotherapy regimens for metastatic bladder cancer in cisplatin ineligible