Bladder cancer is the sixth most prevalent cancer in the United States1. As of 2023, 82,290 new diagnoses of bladder cancer (62,420 in men and 19,870 in women) were documented, as well as 16,710 deaths.2 The median age at diagnosis of bladder cancer is 73 years, and approximately 1 in 28 individuals will be diagnosed with bladder cancer during their lifetime.2 Early detection of bladder cancer can be challenging because many individuals do not present with any symptoms. The most common – and sometimes only – symptom of bladder cancer is hematuria, or blood in the urine. Other, less common symptoms can include increased frequency of urination, urinary tract infection (UTI), and upper urinary tract infection. 

Bladder cancers predominantly emerge as urothelial carcinomas with papillary tumor morphology. Lesions can be divided into 2 broad categories: non-muscle-invasive bladder cancer (NMIBC), which account for 75% of bladder cancers, and muscle-invasive bladder cancer (MIBC), which account for 25% of total bladder cancer cases. Although patients with NMIBCs have an optimistic 5-year prognosis, those with MIBCs usually have less-favorable outcomes.3 Early detection and appropriate treatment by tumor staging are essential for effective management and remission.

 Photomicrograph of transitional cell carcinoma of the bladder.
Photomicrograph of transitional cell carcinoma of the bladder. Credit: Getty Images.

Staging of Bladder Cancer

Oncology treatment guidelines are highly dependent on pathologic stage and severity of illness. For this reason, it is important to clearly identify the staging criteria. Tumors are described based on their size and local spread (T), whether they have invaded the surrounding lymph nodes (N), and whether they have metastasized (M), at which time the cancer has spread to organs far from the original tumor.4 

Following the letters, a number is used to denote severity, with higher numbers reflecting greater severity. This is with the exception of NMIBCs or stage 0 tumors, for which the tumors have descriptive identifiers. 

Stage 0 (0a and 0is)

  • All NMIBC tumors are stage 0
  • Stage 0a includes papillary carcinomas 
  • Grading for stage 0a is Ta, N0, M0
  • Stage 0is denotes flat carcinomas in situ (CIS)
  • Grading for 0is is Tis, N0, M0

Stage I

  • Tumor has started to grow into the connective tissue but is still well contained
  • Grading is T1, N0, M0

Stage II

  • Tumor has spread into the muscle wall of the bladder but has not passed it
  • Grading for tumor that has spread to the inner muscle wall is T2a, N0, M0
  • Grading for tumor that has spread to the outer muscle wall is T2b, N0, M0

Stage IIIA

  • Tumors that have spread and have either passed through the muscle of the bladder to surrounding organs but have not spread into the lymph nodes or have not spread past the bladder muscle and have spread into 1 lymph node
  • Staging can be T(3a, 3b, or 4a), N0, M0
  • If 1 lymph node has cancer, staging can be T1-4a, N1, M0

Stage IIIB

  • Tumors that have or have not spread past the muscle of the bladder to the surrounding organs and have spread to at least 2 lymph nodes
  • Staging can be T1-4a, N2 or N3, M0

Stage IVA

  • Tumors that have spread to the abdominal wall but may or may not have spread to any lymph nodes and have not metastasized
  • Staging for these tumors can be T4b, N0-3, M0
  • Stage IVA can also be tumors that have not spread past the bladder or to nearby lymph nodes but have metastasized to distant lymph nodes
  • Staging for these tumors can be T1-4b, N0-3, M1a

Stage IVB

  • Stage IVB tumors can be at any stage of spreading to nearby organs and lymph nodes but must have spread to at least 1 distant organ
  • Staging is T1-4b, N0-3, M1b

Bladder Cancer Treatment Types

Following diagnostic evaluation (computed tomography [CT] or magnetic resonance imaging [MRI]), all patients with suspected NMIBC are advised to undergo transurethral resection of bladder tumor (TURBT), which is a surgical procedure that removes as much of the lesion as possible and to obtain a pathology specimen for tumor staging. 

Prior to and following this procedure, a range of pharmacotherapeutic treatments are recommended based on stage of illness. Broadly, these treatments fall into 3 categories: chemotherapy, immunotherapy, and targeted therapy. Treatments can be delivered systemically (ie, via intravenous infusion) or through intravesical instillation, which are infusions delivered to the bladder via urethral catheter.5,6 

Chemotherapy

Chemotherapeutic drugs damage DNA or impair DNA synthesis, forcing fast-growing cells to enter into apoptosis, or programmed cell death.

The following is a listing of chemotherapeutic agents approved by the US Food and Drug Administration for use in bladder cancer:

  • Cisplatin
  • Doxorubicin hydrochloride
  • Fluorouracil 
  • Gemcitabine
  • Mitomycin
  • Thiotepa
  • Valrubicin

Immunotherapy

Immunotherapies are a broad class of agents that generally work by activating the immune system to destroy cancerous cells. In bladder cancer, these include monoclonal antibody treatments, antibody-drug conjugates, and live-attenuated bacterial infusions. Monoclonal antibody treatments such as avelumab, nivolumab, and pembrolizumab work by blocking the activity of programmed death-1/programmed death ligand-1 (PD-1/PD-L1), a molecular pathway that shields cancer cells from the immune system. Antibody-drug conjugates (enfortumab vedotin-ejfy and scituzumab govitecan-hziy) are monoclonal antibodies that are covalently attached to a chemotherapy drug. 

The following is a listing of FDA-approved immunotherapies for use in bladder cancer:

  • Avelumab
  • Bacillus Calmette-Guérin (BCG)
  • Enfortumab vedotin-ejfy
  • Nivolumab
  • Pembrolizumab
  • Sacituzumab govitecan-hziy

Targeted Therapy

Targeted therapies are designed to block specific genetic or molecular pathways that are disrupted in cancer cells. Examples include gene therapies and kinase inhibitors. 

The following is a listing of FDA-approved targeted therapies for use in bladder cancer:

  • Erdafitinib
  • Nadofaragene firadenovec-vncg

Combination Therapies

As the name suggests, combination therapies combine multiple FDA-approved pharmacotherapies to optimize treatment of a disease. This is most frequently recommended as systemic chemotherapy during late-stage disease. 

The following is a listing of FDA-approved, recommended combination therapies for bladder cancer:

  • Gemcitabine-cisplatin
  • Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC)
  • High-dose MVAC
  • Pembrolizumab with enfortumab

When and How To Use Different Treatments for Bladder Cancer

Different treatments are recommended based on stage of disease, size of lesion, and responsiveness to previous treatment. 

The following tables review dosage, administration, treatment duration, and recommended use based on stage of disease for each of the 3 treatment categories.

Table 1. Management Guidelines for Chemotherapies for Bladder Cancer

DrugProprietary Name(s)DosageAdministrationTreatment DurationRecommended Use (Stage)
Cisplatin50 mg/m2 to 70 mg/mevery 3 to 4 wkIV infusion over 6 h6 wkAdvanced disease, stages II and III prior to surgery, stages IVa and IVb
Doxorubicin hydrochlorideAdriamycin60 mg/m2 to 75 mg/m2 every 21 dIV infusion3-6 cyclesAdvanced disease, stages IVa and IVb
Fluorouracil*Not indicatedIV infusionNot indicatedAdvanced disease, stage IVb, palliative care
GemcitabineGemzar500 to 3600 mg/m2Intravesical instillation6 wkNon-advanced, stages 0 and I
MitomycinJelmyto4 mg/mL every 6 wkIntravesical instillationUp to 11 additional treatmentsNon-advanced, stages 0 and I
Thiotepa*Tepadina60 mg in 30 to 60 mL of NaClInjection to bladder via urethral catheterNot indicatedNon-advanced, stage 0
ValrubicinValstar800 mg once a wkIntravesical instillation6 wkNon-advanced, stage 0, refractory CIS

IV = intravenous; CIS = carcinoma in situ; NaCl = sodium chloride.

*Not recommended in any setting by NCCN.

From FDA-approved prescribing information.7-12 

Table 2. Management Guidelines for Immunotherapies for Bladder Cancer

DrugProprietary Name(s)DoseAdministrationTreatment DurationRecommended Use (Stage)
AvelumabBavencio800 mg every 2 wk Intravenous infusion over 60 minUntil disease advances or toxicity becomes intolerableAdvanced disease, stage Ivb
BCG1 vial (50 mL total volume)Intravesical instillation (held in bladder for 2 h prior to urination)6-wk course followed by maintenance therapy for 3 wk at months 3, 6, 12, 18, 24, 30, and 36Non-advanced, stages 0 and I
Enfortumab vedotin-ejfyPadcev1.25 mg/kg (maximum of 125 mg) on days 1,8, and 15 of 28-d treatment cycleIntravenous infusion over 30 minUntil disease advances or toxicity becomes intolerableAdvanced disease, stage Ivb
NivolumabOpdivo240 mg every 2 wk or 480 mg every 4 wkIntravenous infusion over 30 minUntil disease advances or toxicity becomes intolerable for up to 1 yAdvanced disease, stages II and II postsurgery, stage Ivb
PembrolizumabKeytruda200 mg every 3 wk  or 400 mg every 6 wkIntravenous infusion over 30 minUntil disease advances or toxicity becomes intolerableAdvanced disease, stage IVb, and recurrent bladder cancer
Sacituzumab govitecan-hziyTrodelvy10 mg/kg weekly on days 1 and 8 of 21-d treatment cycleIntravenous infusionUntil disease advances or toxicity becomes intolerableAdvanced disease, stage IV

BCG = Bacillus Calmette-Guérin; IV = intravenous.

From FDA-approved prescribing information.13-18

Table 3. Management Guidelines for Targeted Therapies for Bladder Cancer

DrugProprietary Name(s)DoseAdministrationTreatment DurationRecommended Use (Stage)
ErdafitinibBalversa8 mg once daily; can be increased to 9 mg at 3 wk if phosphate levels are acceptableTablets taken orallyIndefinitely if toleratedAdvanced disease; used in individuals with specific mutations in FGFR2 or FGFR3
Nadofaragene firadenovec-vncgAdstiladrin; Instilidrin75 mL at a concentration of 3 x 1011 viral particles/mL once every 3 moIntravesical instillation over 1 hUp to 1 yNon-advanced disease but high-risk, BCG-unresponsive CIS

BCG = Bacillus Calmette-Guérin; CIS = carcinoma in situ.

From FDA-approved prescribing information.19,20

Table 4. Management Guidelines for Combination Therapies for Bladder Cancer

Drug CombinationDoseTreatment DurationRecommended Use (Stage)
Gemcitabine-cisplatin1000 mg/m2 of gemcitabine on days 1, 8, and 15 of 28-d cycle and 100 mg/m2 of cisplatin on day 14 cyclesAdvanced disease: stage IIIB, stage IVA, stage IVB, recurrent bladder cancer
MVAC 28-d cycle; 30 mg/m2 of methotrexate on days 1, 15, and 22;3 mg/m2 of vinblastine on days 2, 15, and 22;30 mg/m2 of doxorubicin on day 2; 70 mg/m2 of cisplatin on day 26 cyclesAdvanced disease: stage IIIB, stage IVA, stage IVB, recurrent bladder cancer
High-dose MVAC/ DDMVAC14-day cycle; 30 mg/m2 of methotrexate on day 1;3 mg/m2 of vinblastine on day 2;30 mg/m2 of doxorubicin on day 2; 70 mg/m2 of cisplatin on day 23-6 cyclesAdvanced disease: stage IIIB, stage IVA, stage IVB, recurrent bladder cancer
Pembrolizumab with enfortumab200 mg every 3 wk or 400 mg every 6 wk of pembrolizumab; 1.25 mg/kg of enfortumab on days 1 and 8 of a 21-d cycle; enfortumab given first if both agents are administered on the same dayUntil disease advances or toxicity becomes intolerable for up to 24 moAdvanced disease: stages II and II postsurgery, stage IVb

MVAC = methotrexate, vinblastine, doxorubicin, and cisplatin; DDMVAC = double-dose MVAC.

From FDA-approved prescribing information.17,18

Monitoring Side Effects of Bladder Cancer Treatment

Adverse effects from pharmacotherapeutic treatments are a primary reason to modify or discontinue a treatment regimen. Generally, chemotherapy can cause toxicity to unintended organs. Chemotherapy damages fast-growing cells; while cancerous cells are rapidly growing and dividing, healthy cell types such as those in hair, skin, and the gastrointestinal tract also grow quickly. Thus, these cells are also often susceptible to chemotherapy-induced cell death.

Any medication that enters the bloodstream will have the potential to impair the liver and kidneys, as these organs remove harmful metabolites from the bloodstream.

Although locally contained, intravesical instillation of any treatment through a urethral catheter can cause the patient to experience discomfort and irritation.

The following tables review common side effects, side effects that require treatment discontinuation or modification, and drug-drug interactions associated with treatments for bladder cancer, as well as clinical considerations for special populations.

Table 5. Side Effect Profiles for Chemotherapies for Bladder Cancer

DrugMost Common Adverse EventsSide Effects Requiring Treatment Discontinuation or Modification Drug-Drug InteractionsSpecial Populations
CisplatinRenal toxicity, ototoxicity, myelosuppressionNephrotoxicity, neuropathy, ototoxicityAnticonvulsants (less therapeutic), pyridoxine with altretamine Lactating patients should not breastfeed; not recommended during pregnancy; increased likelihood of renal failure in elderly patients
Doxorubicin hydrochlorideCardiomyopathy and arrhythmias, secondary malignancies, extravasation and tissue necrosis, severe myelosuppression, tumor lysis syndrome, radiation sensitization and radiation recall Cardiomyopathy, hepatic impairmentInhibitors and inducers of CYP3A4, CYP2D6, and P-gp; paclitaxel; trastuzumab; dexrazoxane; 6-mercaptopurineRisk to fetus; lactation is not recommended; as infertility is possible for both men and women, contraception is recommended for sexually active individuals; higher risk for pediatric population 
Fluorouracil Low DPD, cardiotoxicity, hyperammonemic encephalopathy, neurologic toxicity, diarrhea, hand-foot syndrome, myelosuppression, inflammation of the oral mucosa, increased risk of elevated INR with warfarinLow DPD, cardiotoxicity, hyperammonemic encephalopathy, neurologic toxicity, diarrhea, hand-foot syndrome, myelosuppression, inflammation of the oral mucosa, increased risk of elevated INR with warfarinAnticoagulants and CYP2C9 substratesRisk to fetus; lactation is not recommended; as infertility is possible for both men and women, contraception is recommended for sexually active individuals; patients of childbearing potential should refrain from getting pregnant for 3 mo following treatment
GemcitabineHematologic, pulmonary, renal, hepaticPulmonary toxicity, renal toxicityNone indicatedEmbryotoxic; not recommended in pregnant or lactating patients
MitomycinUreteric obstruction, flank discomfort, UTI, hematuria (blood in urine), abdominal discomfort, fatigue, renal dysfunction, nausea, dysuria (painful urination), vomiting Ureteric obstruction (58%), bone marrow suppressionNone indicatedNot recommended in pregnant patients; can cause fetal harm; lactating individuals should wait 1 wk following the last treatment to breastfeed
ThiotepaMyelosuppression, hypersensitivity, cutaneous toxicity, hepatic veno-occlusive disease, neural toxicity,  carcinogenicity Anaphylaxis, nervous system toxicityCytochrome CYP3A inhibitors and inducers, cytochrome CYP2B6 substratesCould cause harm to a fetus; lactation is not recommended during treatment; men should be advised to use contraception for at least 1 y after discontinuation of use; women should be advised to use contraception for at least 6 mo after discontinuation of use
ValrubicinUrinary frequency, dysuria, urinary urgency, bladder spasm, hematuria, bladder pain, urinary incontinenceNone indicatedNone indicatedCould cause harm to fetus; lactating patients should not breastfeed during treatment and for 2 wk after discontinuation of use

UTI = urinary tract infection; DPD = dipyrimidine dehydrogenase; INR = international normalized ratio; P-gp = P-glycoprotein.

From FDA-approved prescribing information.5-10 

Table 6. Side Effect Profiles for Immunotherapies for Bladder Cancer

DrugMost Common Adverse EventsSide Effects Requiring Treatment Discontinuation or Modification Drug-Drug InteractionsSpecial Populations
AvelumabSevere and fatal immune-mediated reactions, infusion-related reactions, complications of allogeneic HSCT, major cardiovascular eventsImmune-mediated reactions, infusion-related reactions, cardiovascular eventsNone indicatedCan cause harm to fetuses; approved for use in pediatric patients older than 12 y
BCGDysuria, urinary frequency, flu-like syndrome, hematuria, fever Fever and acute febrile illnessImmunosuppressants; bone marrow depressants; radiation; antimicrobial therapy may interfere with efficacy Not recommended for pregnant or lactating patients
Enfortumab vedotin-ejfySkin reactions, hyperglycemia, pneumonitis, peripheral neuropathy, ocular disorders, infusion site extravasationPneumonitis, peripheral neuropathy, hyperglycemiaUse of enfortumab in conjunction with dual P-gp and potent CYP3A4 inhibitors may result in increased exposure to MMAENot for use in patients with moderate or severe hepatic impairment; not advised for patients who are lactating; can cause harm to fetuses
NivolumabFatigue, rash, musculoskeletal discomfort, skin itching, diarrhea, nausea, weakness, cough, labored breathing, constipation, reduced appetite, back pain, joint pain, upper respiratory tract infection, fever, headache, abdominal pain, vomiting, UTIImmune-mediated reactions, infusion-related reactionsNone indicatedCould cause harm to fetus; lactating patients should not breastfeed for at least 5 mo after discontinuation of use
PembrolizumabFatigue, musculoskeletal discomfort, skin itching, rash, nausea, reduced appetite, hyperglycemia, anemia, lymphopenia, hypoalbuminemia, hyponatremia, elevated alkaline phosphatase and creatinine, hypophosphatemia, elevated liver enzymes, hyperkalemia, hypocalcemiaImmune-mediated reactions, infusion-related reactionsNone indicatedCould cause harm to fetus; lactating patients should not breastfeed for at least 4 mo after discontinuation of use
Sacituzumab govitecan-hziyDecreased leukocytes, neutrophils, lymphocytes, and hemoglobin; diarrhea; nausea; fatigue; hair loss; constipation; elevated glucose; decreased albumin; vomiting; reduced appetite; reduced creatinine clearance; elevated alkaline phosphatase; reduced magnesium, potassium, and sodiumInfusion-related reactions, neutropenia, nausea/vomiting, diarrheaUGT1A1 inhibitors and inducersCould cause harm to a fetus; lactating patients should not breastfeed for at least 1 month after discontinuation of use; men should be advised to use contraception for 3 months after discontinuation of use; women should be advised to use contraception for 6 months after discontinuation of use

BCG = Bacillus Calmette-Guérin; HSCT = hematopoietic stem cell transplantation; AST = aspartate aminotransferase; MMAE = monomethyl auristatin E; P-gp = P-glycoprotein; UTI = urinary tract infection.

From FDA-approved prescribing information.11-16

Table 7. Side Effect Profiles for Targeted Therapies for Bladder Cancer

DrugMost Common Adverse Events (>20%)Side Effects Requiring Treatment Discontinuation or Modification Drug-Drug InteractionsSpecial Populations
ErdafitinibElevated phosphate, inflammation of the oral mucosa, fatigue, elevated creatinine, diarrhea, dry mouth, nail disorders, elevated liver enzymes, elevated alkaline phosphatase, reduced sodium, reduced appetite, reduced albumin, dysgeusia, reduced hemoglobin, dry skin, reduced magnesium, dry eye, hair loss, palmar-plantar erythrodysesthesia syndrome, constipation, reduced phosphate, abdominal discomfort, elevated calcium, nausea, musculoskeletal discomfortOcular disorders, hyperphosphatemia, soft tissue mineralizationModerate CYP2C9 or strong CYP3A4 inhibitors, moderate or strong CYP2C9 and CYP3A4 inducers, agents that alter serum phosphate levels, CYP3A4 substrates, OCT2 substrates, P-gp substratesBreastfeeding is not recommended; could cause harm to a fetus; men with female sexual partners should use appropriate contraception
Nadofaragene firadenovec-vncgIncreased glucose, discharge at instillation site, elevated triglycerides, fatigue, bladder spasms, urinary urgency, elevated creatinine, hematuria, reduced phosphate, chills, fever, painful urinationBladder spasm; instillation site discharge, benign bladder neoplasmUGT1A1 inhibitors or inducersAvoid use in immunocompromised patients; pregnant patients should be advised on risk to fetus

OCT2 = organic cation transporter 2; P-gp = P-glycoprotein.

From FDA-approved prescribing information.1,21

Guidelines for the Management of Bladder Cancer

Guidelines for the pharmacotherapeutic treatment of bladder cancer consider the following factors:

  • Size of the tumor
  • Whether the tumor has invaded the muscle
  • What surrounding organs have been invaded
  • Whether the cancer has spread to local lymph nodes
  • Whether and the extent to which the tumor has metastasized
  • Previous treatments (including surgery and radiation)
  • Previous responsiveness to treatments
  • Individual health history

Depending on the severity of disease, the goals for treatment may change. For NMIBC, the predominant objective is to prevent recurrence and cease illness advancement. For MIBC, goals are modified to increase the patient’s chance of recovery. Once the tumor has metastasized, treatment goals are more palliative to improve length and quality of life.1 In accordance with treatment recommendations established by the National Cancer Institute and the National Comprehensive Cancer Network, 1,3 the following recommendations are presented by stage of illness.

Bladder Cancer Stages 0 and I 

All patients are recommended to undergo TURBT. Some may also choose to have a partial or full cystectomy, a surgical procedure to remove the bladder. Patients can receive intravesical chemotherapy during the surgical procedure. Options for intravesical chemotherapy during surgery are mitomycin and gemcitabine.

Following surgery, intravesical maintenance therapy with BCG may be recommended. If patients do not tolerate or respond well to BCG, they can receive intravesical chemotherapy with mitomycin and gemcitabine. In response to ongoing BCG shortages, vials of BCG can be divided into thirds; however, the lower dose is not as effective as the full dose. In this case, intravesical chemotherapy is also recommended.

Following TURBT, patients will be assessed for relative future risk. NMIBCs are categorized as low, intermediate, or high risk,1 with appropriate treatment guidelines based on that categorization.

Low Risk

  • A single session of intravesical chemotherapy is recommended during TURBT
  • Surveillance

Intermediate Risk

  • Management with intravesical therapy is preferred
  • BCG is the intravesical therapy of choice
  • Intravesical mitomycin and gemcitabine are recommended when BCG is not tolerated or unavailable

High Risk

  • If there are no very-high-risk features, BCG is preferred but cystectomy is an option
  • If there are very-high-risk features, cystectomy is preferred but BCG is an option
  • If patient is unresponsive to BCG, cystectomy is preferred but intravesical chemotherapy with gemcitabine or mitomycin can be given
  • If patient is unresponsive to BCG and has CIS, intravesical valrubicin can be given
  • If patient is unresponsive to BCG, has Tis, and does not undergo cystectomy (either by choice or eligibility), pembrolizumab is recommended
  • If patient is unresponsive to BCG and has CIS or Ta/T1 tumor, intravesical nadofaragene firadenovec-vncg can be used

During stages 0 and I of bladder cancer, for any instance in which intravesical chemotherapy is used, gemcitabine is usually favored due to tolerability and cost.1

Bladder Cancer Stages II and III 

During stages II and III of bladder cancer, radical cystectomy —  surgery to remove the bladder and surrounding organs — is usually recommended. Radiation and systemic chemotherapy are also recommended at this time. Prior to surgery, chemotherapy with cisplatin is recommended. Postoperatively, adjuvant therapy or immunotherapy with nivolumab is recommended when there is a high risk of cancer recurrence. Adjuvant therapy refers to any systemic pharmacotherapeutic treatment administered postoperatively.

If patients do not undergo surgery, either by choice or because they are medically unable, radiation is recommended in combination with chemotherapy (such as cisplatin or fluorouracil).3

Stage II

  • Combination systemic cisplatin chemotherapy followed by radical cystectomy and postoperative adjuvant treatment is the most recommended stage II bladder cancer treatment
  • In select patients with no Tis and highly localized tumors, combination cisplatin chemotherapy followed by partial cystectomy and postoperative adjuvant treatment is recommended
  • For patients who cannot receive cisplatin-based chemotherapy, cystectomy alone is recommended with postoperative adjuvant treatment
  • Following any type of cystectomy, if no previous cisplatin-based therapy has been used, MVAC for 3 to 6 cycles is recommended
  • Following any type of cystectomy, if the patient has received previous cisplatin-based therapy or is more concerned with delaying recurrence rather than curing disease, nivolumab is recommended
  • Patients who choose radiation with chemotherapy and no surgery should receive systemic cisplatin and can subsequently receive intravesical or systemic chemotherapy if tumor persists1

Stage IIIA

  • Combination systemic cisplatin chemotherapy followed by radical cystectomy and postoperative adjuvant treatment is the most recommended stage IIIA bladder cancer treatment
  • For patients who cannot receive cisplatin-based chemotherapy, cystectomy alone is recommended with postoperative adjuvant treatment
  • Following any type of cystectomy, if no previous cisplatin-based therapy has been used, MVAC for 3 to 6 cycles is recommended
  • Following any type of cystectomy, if the patient has received previous cisplatin-based therapy or is more concerned with delaying recurrence rather than curing disease, nivolumab is recommended
  • Patients who choose radiation with chemotherapy and no surgery should receive systemic cisplatin and can subsequently receive intravesical or systemic chemotherapy if tumor persists1

Stage IIIB

  • Systemic chemotherapy with gemcitabine and cisplatin followed by avelumab for maintenance therapy is recommended
  • If patients undergoing systemic chemotherapy are not eligible for cisplatin-containing therapies, gemcitabine and carboplatin are recommended 
  • If patients undergoing systemic chemotherapy are not eligible for any platinum-containing therapies, pembrolizumab is recommended
  • If patients undergoing systemic chemotherapy are not eligible for any platinum-containing therapies and their tumors express PD-L1, atezolizumab is recommended
  • If radiation is used in addition to systemic chemotherapy, cisplatin is recommended or low-dose gemcitabine is recommended if the patient is not eligible for cisplatin-containing therapies1

Stage IVA

At this advanced stage, systemic, combinatorial chemotherapies are recommended. MVAC; high-dose MVAC; and cisplatin, methotrexate, and vinblastine are all recommended for stage IVA bladder cancer. If the patient decides to undergo surgery, cisplatin is recommended prior to surgery. If the patient opts for radiation, cisplatin and fluorouracil should also be administered. Other surgical options available are for palliative care.3

  • For M0 and M1a disease, systemic chemotherapy with gemcitabine and cisplatin followed by avelumab for maintenance therapy is recommended
  • If patients undergoing systemic chemotherapy are not eligible for cisplatin-containing therapies, gemcitabine and carboplatin are recommended 
  • If patients undergoing systemic chemotherapy are not eligible for any platinum-containing therapies, pembrolizumab is recommended
  • If patients undergoing systemic chemotherapy are not eligible for any platinum-containing therapies and their tumors express PD-L1, atezolizumab is recommended
  • M0 disease can also be treated with radiation and cisplatin alone or low-dose gemcitabine if the patient is not eligible for cisplatin-containing therapies1

Stage IVB

At this advanced stage, systemic, combinatorial chemotherapies are recommended. MVAC; high-dose MVAC; and cisplatin, methotrexate, and vinblastine are all recommended for stage IVB bladder cancer, similar to the recommendation for stage IVA bladder cancer. Gemcitabine with cisplatin or carboplatin is also recommended for stage IVB bladder cancer. Immunotherapies such as avelumab, nivolumab, or pembrolizumab can be used at this time. Other surgical and radiation options are available for palliative care.3

  • For metastatic, M1b disease, systemic chemotherapy with gemcitabine and cisplatin followed by avelumab for maintenance therapy is recommended
  • If patients undergoing systemic chemotherapy are not eligible for cisplatin-containing therapies, gemcitabine and carboplatin are recommended 
  • If patients undergoing systemic chemotherapy are not eligible for any platinum-containing therapies, pembrolizumab is recommended
  • If patients undergoing systemic chemotherapy are not eligible for any platinum-containing therapies and their tumors express PD-L1, atezolizumab is recommended
  • Palliative care with radiation or surgery may also be recommended1

Recurrent Bladder Cancer

For persistent, recurrent bladder cancers, more aggressive treatment strategies can be employed. Systemic, combinatorial chemotherapies are recommended. MVAC; high-dose MVAC; cisplatin, methotrexate, and vinblastine; and gemcitabine with cisplatin or carboplatin are all combinatorial chemotherapy options for recurrent bladder cancer. Targeted treatments — including enfortumab vedotin, erdafitinib, or ramucirumab — may be appropriate for this situation.3

  • If the tumor is Tis, Ta, or T1, intravesical therapy with BCG is recommended
  • Cystectomy and TURBT can also be options for recurrent Tis, Ta, and T1 tumors
  • If the recurrent tumor has invaded muscle, cystectomy is recommended
  • If the muscle-invasive tumor is not operable, radiation and cisplatin alone or low-dose gemcitabine if patient is not eligible for cisplatin-containing therapies is recommended
  • Muscle-invasive tumors can also be eligible for systemic chemotherapy (recommendations for advanced systemic chemotherapy have been described above)1

References

1. NCCN Clinical practice guidelines in oncology (NCCN Guidelines), bladder cancer. National Comprehensive Cancer Network. Updated February 9, 2023. Accessed April 18, 2023. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

2. Key statistics for bladder cancer. American Cancer Society. Updated January 13, 2023. Accessed May 2, 2023. https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html

3. Bladder cancer stages. American Cancer Society. Updated January 30, 2019. Accessed April 19, 2023. https://amp.cancer.org/cancer/bladder-cancer/detection-diagnosis-staging/staging.html

4. Bladder cancer prognosis and survival rates. National Cancer Institute. Updated February 16, 2023. Accessed April 18, 2023. https://www.cancer.gov/types/bladder/survival

5. Bladder cancer treatment. National Cancer Institute. Updated February 16, 2023. Accessed April 18, 2023. https://www.cancer.gov/types/bladder/treatment

6. Cisplatin. Prescribing Information. Fresenius Kabi USA, LLC; 2017. Updated December 31, 2019. Accessed April 18, 2023. 

7. Doxorubicin Hydrochloride. Prescribing information. Amneal Pharmaceuticals LLC; 1974. Updated February 25, 2021. Accessed April 18, 2023. 

8. Fluorouracil. Prescribing information. Spectrum Pharmaceuticals, Inc.; 1962. Updated July 2016. Accessed April 18, 2023. 

9. Gemzar. Prescribing information. Eli Lilly and Company; 1996. Accessed April, 18, 2023. 

10. Jelmyto. Prescribing information. UroGen Pharma, Inc; 1974. Updated August 2020. Accessed April 18, 2023. 

11. Thiotepa. Prescribing information. MSN Private Laboratories Private Limited; 1959. Updated November 2019. Accessed April 18, 2023. 

12. Valstar. Prescribing information. Endo Pharmaceuticals Solutions Inc.; 1981. Updated October 2019. Accessed April 18, 2023. 

13. Bavencio. Prescribing information. EMD Serono, Inc.; 2017. Updated July 20, 2022. Accessed April 18, 2023. 

14. BCG. Prescribing information. Organon; 1990. Updated 2009. Accessed April 18, 2023. 

15. Padcev. Prescribing information. Seagen Inc.; 2019. Updated April 1, 2023. Accessed April 18, 2023. 

16. Opdivo. Prescribing information. E.R. Squibb & Sons, LLC.; 2014. Updated February 2023. Accessed April 18, 2023. 

17. Keytruda. Prescribing information. Merck Sharp & Dohme LLC.; 2014. Updated April 3, 2023. Accessed April 18, 2023. 

18. Trodelvy. Prescribing information. Gilead Science; 2020. Updated February 9, 2023. Accessed April 18, 2023. 

19. Balversa. Prescribing information. Janssen Products LP; 2019. Updated February 3, 2023. Accessed April 18, 2023. 

20. Adstiladrin. Prescribing information. Ferring Pharmaceuticals; 2022. Updated December 2022. Accessed April 18, 2023. 

21. Zhu C, Liu J, Zhang J, et al. Efficacy and safety of dose-dense chemotherapy in urothelial carcinoma. Oncotarget. 2017;8(41):71117-71127.

Author Bio

Hannah Actor-Engel, PhD earned a Bachelor of Science degree in Neural Science at New York University, and she received her PhD in Neuroscience at the University of Colorado. She is a multidisciplinary neuroscientist who is passionate about scientific communication and improving global health through biomedical research.