Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

non-muscle-invasive tumours

1st line – transurethral resection of bladder tumour

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ACUTE
|
non-muscle-invasive tumours
|
low risk
1st line – 

transurethral resection of bladder tumour

American Urological Association/Society of Urologic Oncology (AUA/SUO) non-muscle-invasive bladder cancer (NMIBC) guidelines define low risk as: solitary, small-volume (≤3 cm), low-grade Ta disease (Ta = non-invasive papillary carcinoma); any papillary urothelial neoplasm of low malignant potential.[60]

Transurethral resection of a bladder tumour (TURBT) is first-line therapy for low-risk non-muscle-invasive tumours. Guidelines recommend repeat transurethral resection within 6 weeks to lower recurrence if the initial resection was incomplete.​[21][60]

Patients with non-muscle-invasive bladder tumours and co-existing obstructive benign prostatic hyperplasia may have transurethral resection of the prostate at the same time as TURBT. Meta-analysis demonstrates that performing the procedures simultaneously improves patient quality of life, without any risk of increasing tumour recurrence or metastasis rates.[113]

Plus – immediate post-operative intravesical chemotherapy

Back
ACUTE
|
non-muscle-invasive tumours
|
low risk
Plus – 

immediate post-operative intravesical chemotherapy

Treatment recommended for ALL patients in selected patient group

An immediate, single instillation of intravesical chemotherapy (administered within 24 hours of transurethral resection) is recommended to reduce the risk of recurrence.[60]​​

Gemcitabine and mitomycin are commonly used.[61] Gemcitabine is preferred; it has favourable tolerability and may reduce the risk of recurrence and progression over time compared with mitomycin.[61][93][94]​​ Epirubicin is an alternative option.[60][61][95]

Instillation should not be done if bladder perforation is suspected or resection is extensive.

See local specialist protocol for dosing guidelines.

Primary options

gemcitabine

OR

mitomycin

Secondary options

epirubicin

1st line – transurethral resection of bladder tumour

Back
ACUTE
|
non-muscle-invasive tumours
|
intermediate risk
1st line – 

transurethral resection of bladder tumour

American Urological Association/Society of Urologic Oncology (AUA/SUO) non-muscle-invasive bladder cancer (NMIBC) guidelines define intermediate risk as: large-volume (>3 cm) or multifocal low-grade Ta disease; high-grade Ta disease ≤3 cm; low-grade T1 disease; or recurrence of Ta tumour within 1 year (Ta = non-invasive papillary carcinoma; T1 = tumour invades subepithelial connective tissue, i.e., the lamina propria).[60] These patients have a high risk of recurrence but a low risk of disease progression.

Transurethral resection of a bladder tumour (TURBT) is first-line therapy for intermediate-risk non-muscle-invasive tumours. Guidelines recommend repeat transurethral resection within 6 weeks to lower recurrence if the initial resection was incomplete, there is no detrusor muscle in the initial resection specimen, or if T1 tumours are found.​[21][60]

Patients with non-muscle-invasive bladder tumours and co-existing obstructive benign prostatic hyperplasia may have transurethral resection of the prostate at the same time as TURBT. Meta-analysis demonstrates that performing the procedures simultaneously improves patient quality of life, without any risk of increasing tumour recurrence or metastasis rates.[113]

Plus – immediate post-operative intravesical chemotherapy

Back
ACUTE
|
non-muscle-invasive tumours
|
intermediate risk
Plus – 

immediate post-operative intravesical chemotherapy

Treatment recommended for ALL patients in selected patient group

An immediate, single post-operative instillation of intravesical chemotherapy (administered within 24 hours of transurethral resection) is recommended to reduce the risk of recurrence.[60]​​[94]​​​​​[95]

Gemcitabine and mitomycin are commonly used.[61] Gemcitabine is preferred; it has favourable tolerability and may reduce the risk of recurrence and progression over time compared with mitomycin.[61][93][94] Epirubicin is an alternative option.[60][61]​​[95]

Instillation should not be done if bladder perforation is suspected or resection is extensive.

Bacillus Calmette-Guérin (BCG) is never appropriate for immediate post-operative instillation owing to the risk of sepsis.[96]

See local specialist protocol for dosing guidelines.

Primary options

gemcitabine

OR

mitomycin

Secondary options

epirubicin

Plus – delayed intravesical Bacillus Calmette-Guérin (BCG) immunotherapy or intravesical chemotherapy

Back
ACUTE
|
non-muscle-invasive tumours
|
intermediate risk
Plus – 

delayed intravesical Bacillus Calmette-Guérin (BCG) immunotherapy or intravesical chemotherapy

Treatment recommended for ALL patients in selected patient group

Delayed intravesical BCG immunotherapy or intravesical chemotherapy may be considered for patients with intermediate-risk disease, starting 3-4 weeks after transurethral resection and administered every week for 6 weeks.[60][61]​ 

Decisions about additional intravesical therapy are based on assessment of risk of recurrence, patient history and symptoms, risks of adverse outcomes from repeat resection, and toxicity of therapy.[60]

Maintenance therapy is an option if there is a complete response to delayed treatment.[60][61] The optimal duration of maintenance therapy is not known. Guidelines specify using BCG maintenance for 1 year in intermediate-risk disease.[60][61][97]​ A 3-week BCG regimen given at 3, 6, and 12 months is commonly used.[61][98]

Patients with persistent or recurrent disease after a single course of induction intravesical BCG may be offered a second course of BCG.[60]

Mitomycin and gemcitabine are commonly used alternatives to BCG for delayed intravesical therapy. Gemcitabine is preferred; it has favourable tolerability and may reduce the risk of recurrence and progression over time compared with mitomycin.[61] Other options include sequential gemcitabine plus docetaxel, epirubicin, valrubicin, docetaxel, or sequential gemcitabine plus mitomycin.[61] Docetaxel is well tolerated intravesically and is an effective option for BCG-refractory non-muscle-invasive bladder cancer alone and in combination with gemcitabine.[99][100]​ Chemotherapy maintenance is commonly given at monthly intervals for 6-12 months.​[60]

See local specialist protocol for dosing guidelines.

Primary options

BCG live intravesical

Secondary options

mitomycin

OR

gemcitabine

Tertiary options

gemcitabine

and

docetaxel

OR

epirubicin

OR

valrubicin intravesical

OR

docetaxel

OR

gemcitabine

and

mitomycin

1st line – transurethral resection of bladder tumour

Back
ACUTE
|
non-muscle-invasive tumours
|
high risk
1st line – 

transurethral resection of bladder tumour

American Urological Association/Society of Urologic Oncology (AUA/SUO) non-muscle-invasive bladder cancer (NMIBC) guidelines define high risk as: carcinoma in situ (CIS; Tis): high-grade Ta >3 cm or multifocal; high-grade T1; any recurrent high-grade Ta tumour; any Bacillus Calmette-Guérin (BCG) failure in a high-grade patient; any subtype (variant) histology or lymphovascular or prostatic urethral invasion.[60]

Transurethral resection is first-line therapy for high-risk non-muscle-invasive tumours, followed by induction and maintenance BCG immunotherapy.[60]

Completeness of tumour resection, recurrence at 3 months, and the presence of residual disease at repeat resection all have important prognostic significance.[103][104]​ 

Guidelines recommend repeat transurethral resection within 6 weeks to lower recurrence if the initial resection was incomplete, there is no detrusor muscle in the initial resection specimen, T1 tumours are found, or tumours have subtype (variant) histology (and the patient is not having cystectomy).​[21][60]​​​ Repeat resection will disclose residual tumour in about 50% to 70% of patients with T1 tumours.[60] Residual T1 disease on repeat resection has been associated with increased incidence of muscle invasion and higher risk for early tumour progression compared with no tumour or non-T1 tumour on resection.[105]

Repeat resection should be considered for high-risk, high-grade Ta tumours.[60][61]​​[106][107]​​​

Patients with non-muscle-invasive bladder tumours and co-existing obstructive benign prostatic hyperplasia may have transurethral resection of the prostate at the same time as transurethral resection of a bladder tumour. Meta-analysis demonstrates that performing the procedures simultaneously improves patient quality of life, without any risk of increasing tumour recurrence or metastasis rates.[113]

Consider – immediate post-operative intravesical chemotherapy

Back
ACUTE
|
non-muscle-invasive tumours
|
high risk
Consider – 

immediate post-operative intravesical chemotherapy

Additional treatment recommended for SOME patients in selected patient group

While not confirmed to be beneficial in high-risk disease, immediate, single post-operative (within 24 hours) instillation of intravesical chemotherapy is sometimes used in addition to delayed intravesical immunotherapy.[60][101][102]​ 

Gemcitabine and mitomycin are commonly used.[61] Gemcitabine is preferred; it has favourable tolerability and may reduce the risk of recurrence and progression over time compared with mitomycin.[61][93][94] Epirubicin is an alternative option.[60][61][95]

Instillation should not be done if bladder perforation is suspected or resection is extensive.

Bacillus Calmette-Guérin (BCG) is never appropriate for immediate post-operative instillation owing to the risk of sepsis.[96]

See local specialist protocol for dosing guidelines.

Primary options

gemcitabine

OR

mitomycin

Secondary options

epirubicin

Plus – delayed intravesical Bacillus Calmette-Guérin (BCG) immunotherapy

Back
ACUTE
|
non-muscle-invasive tumours
|
high risk
Plus – 

delayed intravesical Bacillus Calmette-Guérin (BCG) immunotherapy

Treatment recommended for ALL patients in selected patient group

BCG immunotherapy is most commonly given intravesically 3-4 weeks after transurethral resection and retained for 2 hours. Induction is weekly BCG for 6 weeks.[60][61]​​

Maintenance BCG is recommended if there is a complete response to induction. The optimal duration of maintenance therapy is not known. Guidelines specify using BCG maintenance for 3 years, if tolerated, for high-risk disease.[60][61][97] Maintenance therapy is usually given in weekly instillations for 3 weeks at 3, 6, 12, 18, 24, 30, and 36 months.[61] Dose reductions may be used if there are local symptoms or to prevent escalation of BCG adverse effects.[98]

In high-risk patients, full-dose 3-year BCG reduces recurrences compared with full dose BCG for 1 year.[97]

Patients with persistent or recurrent disease after a single course of induction intravesical BCG should be offered a second course of BCG.[60]

See local specialist protocol for dosing guidelines.

Primary options

BCG live intravesical

2nd line – radical cystectomy

Back
ACUTE
|
non-muscle-invasive tumours
|
high risk
2nd line – 

radical cystectomy

Bacillus Calmette-Guérin (BCG) is the preferred treatment option for most high-risk patients (i.e., without very-high-risk features).[61] Care must be taken when selecting patients for cystectomy, especially in the absence of muscle invasion; overall 90-day mortality for cystectomy was 4.7% in one systematic review, with patient factors, age, and comorbidity identified as important risk factors.[108]

Cystectomy constitutes over-treatment in most high-risk patients who do not have muscle invasion. However, guidelines recommend consideration of cystectomy for patients with very high risk of progression.[21][60][61]​​

Guidelines suggest that cystectomy is preferred for patients with any of the following very-high-risk features: BCG unresponsiveness, certain histopathological subtypes (e.g., micropapillary, plasmacytoid, sarcomatoid), lymphovascular invasion, and prostatic urethral involvement of tumour.[60][61]

Cystectomy is the preferred treatment for high-risk patients who are BCG intolerant or have BCG-unresponsive disease (recurrence or progression during or following adequate BCG therapy).[61]

3rd line – clinical trial or rescue intravesical therapy

Back
ACUTE
|
non-muscle-invasive tumours
|
high risk
3rd line – 

clinical trial or rescue intravesical therapy

For patients who are Bacillus Calmette-Guérin (BCG) intolerant or have BCG-unresponsive disease (recurrence or progression during or following adequate BCG therapy) and decline or are unfit for cystectomy, optimal management has not been established.

Patients may be offered enrolment in a clinical trial or an alternative intravesical therapy, such as mitomycin, gemcitabine, gemcitabine plus docetaxel, epirubicin, valrubicin, docetaxel, or gemcitabine plus mitomycin.[60][61]

A gemcitabine-containing intravesical system may be considered for select high-risk, BCG-unresponsive patients with carcinoma in situ.[61][109]​ 

Primary options

mitomycin

OR

gemcitabine

OR

gemcitabine intravesical

More

Secondary options

gemcitabine

and

docetaxel

OR

epirubicin

OR

valrubicin intravesical

OR

docetaxel

OR

gemcitabine

and

mitomycin

3rd line – pembrolizumab or intravesical nadofaragene firadenovec or intravesical nogapendekin alfa inbakicept plus Bacillus Calmette-Guérin (BCG)

Back
ACUTE
|
non-muscle-invasive tumours
|
high risk
3rd line – 

pembrolizumab or intravesical nadofaragene firadenovec or intravesical nogapendekin alfa inbakicept plus Bacillus Calmette-Guérin (BCG)

For patients who are BCG intolerant or have BCG-unresponsive disease (recurrence or progression during or following adequate BCG therapy) and decline or are unfit for cystectomy, optimal management has not been established.

Further options for select patients with high-risk BCG-unresponsive disease include pembrolizumab (a programmed cell death protein-1 [PD-1] inhibitor), nadofaragene firadenovec (a non-replicating adenoviral vector-based gene therapy), or nogapendekin alfa inbakicept (an interleukin-15 receptor agonist) plus BCG.[61]

Pembrolizumab and nadofaragene firadenovec are approved by the Food and Drug Administration (FDA) for patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer with carcinoma in situ (CIS) or with high-grade papillary Ta/T1 only tumours without CIS.[61][110][111] Nogapendekin alfa inbakicept plus BCG is approved by the FDA for patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer with CIS.[61][112]

The pembrolizumab approval stipulates that patients are ineligible for or elect not to undergo cystectomy. Pembrolizumab is given to a patient with CIS within 12 months of completion of adequate BCG therapy.[60]

A subcutaneous formulation of pembrolizumab (pembrolizumab/berahyaluronidase alfa) may be substituted for intravenous pembrolizumab (dosing and administration instructions are different between the formulations).[61]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

OR

pembrolizumab/berahyaluronidase alfa

OR

nadofaragene firadenovec intravesical

OR

nogapendekin alfa inbakicept intravesical

and

BCG live intravesical

locally invasive tumours

1st line – cystectomy with pelvic lymph node dissection

Back
ACUTE
|
locally invasive tumours
|
localised muscle-invasive disease: T2-T4a N0M0 or N1
1st line – 

cystectomy with pelvic lymph node dissection

Radical cystoprostatectomy (in men) or radical cystectomy often accompanied by hysterectomy (in women) is generally required, and it is thought to provide the best chance of cure.[61] Bilateral pelvic lymph node dissection is an essential part of the procedure. Extended node dissection is controversial; evidence of improved survival is equivocal while risk of adverse effects is increased.​[50][61][124][125]​​​​ Severe scarring secondary to previous surgery or treatments, advanced age, or severe comorbidities may preclude pelvic lymph node dissection.

Cystectomy is followed by the formation of a urinary diversion by means of an ileal conduit to the skin, anastomosing the ureters directly to the stoma on the abdominal skin (cutaneous ureterostomy), or by creating an internal reservoir that can be drained by catheter or through the urethra. Relative contraindications to urethral drainage include carcinoma in situ (CIS; Tis) in the prostatic ducts or a positive urethral margin.[61] An orthotopic neobladder provides some function similar to a native bladder but has an increased risk of night-time incontinence and retention requiring intermittent self-catheterisation.

In selected patients with T2 disease, a partial cystectomy may be feasible.[61]​ This requires a solitary tumour, located in an area of the bladder where a minimum clear margin of 2 cm of non-involved urothelium can be achieved (as well as sufficient soft tissue to enable the tumour to be removed without significantly reducing bladder capacity or causing incontinence). Mostly, this is reserved for tumours in the dome of the bladder that have no associated CIS (Tis) in other areas of the bladder. Relative contraindications are lesions in the trigone or bladder neck.

Consider – preoperative chemotherapy ± perioperative immunotherapy

Back
ACUTE
|
locally invasive tumours
|
localised muscle-invasive disease: T2-T4a N0M0 or N1
Consider – 

preoperative chemotherapy ± perioperative immunotherapy

Additional treatment recommended for SOME patients in selected patient group

Preferred treatment options include neoadjuvant cisplatin-based chemotherapy with or without perioperative/sandwich immunotherapy (followed by cystectomy) for eligible patients with T2-T4a disease without lymph node involvement (N0) or with involvement in a single pelvic lymph node (N1).​[50][61][114][115]​​ 

Neoadjuvant platinum-based combination chemotherapy reduces mortality risk without increased peri-operative complications or mortality.[116][117] 

Dose-dense methotrexate plus vinblastine plus doxorubicin plus cisplatin (ddMVAC) is the preferred regimen; toxicity and efficacy are improved compared with traditional MVAC. Gemcitabine plus cisplatin may be an alternative option.[61][118][119][120][121][122] ​

​Tumour downstaging in response to neoadjuvant treatment is associated with improved overall survival.[123]

Adding perioperative immunotherapy to neoadjuvant chemotherapy improves event-free and overall survival compared with neoadjuvant chemotherapy alone.[115] The preferred regimen for perioperative/sandwich therapy is gemcitabine plus cisplatin plus durvalumab before cystectomy, followed by durvalumab after surgery.​[61][115]

See local specialist protocol for dosing guidelines.

Primary options

ddMVAC

methotrexate

and

vinblastine

and

doxorubicin

and

cisplatin

OR

gemcitabine

and

cisplatin

OR

gemcitabine

and

cisplatin

and

durvalumab

Consider – post-cystectomy chemotherapy, immunotherapy, or radiotherapy

Back
ACUTE
|
locally invasive tumours
|
localised muscle-invasive disease: T2-T4a N0M0 or N1
Consider – 

post-cystectomy chemotherapy, immunotherapy, or radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Post-cystectomy adjuvant treatment is recommended for certain patients.[61]

Patients who received perioperative/sandwich therapy should be given durvalumab postoperatively, regardless of pathology.​​​[115]

Patients who received cisplatin-based neoadjuvant chemotherapy who have pathological T2-T4a tumours or positive nodes may be considered for adjuvant nivolumab or pembrolizumab.[126][129][130]​ Subcutaneous formulations of pembrolizumab and nivolumab (pembrolizumab/berahyaluronidase alfa and nivolumab/hyaluronidase) may be substituted for intravenous formulations (dosing and administration instructions are different between the formulations).

Patients who did not receive cisplatin-based neoadjuvant chemotherapy who are node positive or with pathological T3-T4a tumours should be considered for adjuvant chemotherapy with dose-dense methotrexate plus vinblastine plus doxorubicin plus cisplatin (ddMVAC); this is the preferred option.[61] Adjuvant gemcitabine plus cisplatin, nivolumab (or subcutaneous nivolumab/hyaluronidase), or pembrolizumab (or subcutaneous pembrolizumab/berahyaluronidase alfa) are alternative options for these patients.[61][126][127]​​[129][130][131]

Selected high-risk patients (e.g., pathological T3-4, positive nodes, positive margins) may be considered for adjuvant radiation therapy, although evidence for this approach is limited.[61][128][132][133]​ 

See local specialist protocol for dosing guidelines.

Primary options

ddMVAC

methotrexate

and

vinblastine

and

doxorubicin

and

cisplatin

OR

durvalumab

OR

nivolumab

OR

nivolumab/hyaluronidase

OR

pembrolizumab

OR

pembrolizumab/berahyaluronidase alfa

Secondary options

gemcitabine

and

cisplatin

2nd line – maximal transurethral resection + chemoradiotherapy

Back
ACUTE
|
locally invasive tumours
|
localised muscle-invasive disease: T2-T4a N0M0 or N1
2nd line – 

maximal transurethral resection + chemoradiotherapy

​For patients who decline or are not candidates for cystectomy, trimodal organ-preservation therapy (TMT) with the combination of maximal TURBT, chemotherapy, and external beam radiotherapy (EBRT) may be an alternative option.[50][126][134]​​​ Preferred candidates for organ preservation therapy include those with smaller solitary tumours, no nodal involvement, no extensive or multifocal carcinoma in situ, no hydronephrosis, and good pre-treatment bladder function.[50]

Adequate patient counselling of the risks and regular post-treatment surveillance are essential. While one meta-analysis found that TMT was non-inferior to radical cystectomy at <10 years, overall TMT was associated with an increased risk of all-cause and bladder-specific cancer mortality.[135] The proportion of patients treated with multimodal organ-preservation therapy who experience recurrence is uncertain.[126]

Treatment decisions for muscle-invasive recurrence following TMT (e.g., salvage cystectomy, systemic therapy, or palliation) should be individualised and involve the multidisciplinary team.[136]

See local specialist protocol for chemoradiotherapy regimens.

1st line – systemic chemotherapy or chemoradiotherapy

Back
ACUTE
|
locally invasive tumours
|
unresectable locally advanced: T4b or N2-3
1st line – 

systemic chemotherapy or chemoradiotherapy

T4b and N2-3 disease is typically considered unresectable (defined as a fixed bladder mass or positive nodes evident before laparotomy) and is generally treated by chemotherapy alone or chemoradiotherapy.[61]

Patients with T1-T4a N2-3 disease receive downstaging chemotherapy (e.g., gemcitabine plus cisplatin, or dose-dense methotrexate plus vinblastine plus doxorubicin plus cisplatin [ddMVAC]), with reassessment CT imaging at 2-3 months after treatment.[61]

Patients with T4b disease with no metastases are generally treated with chemotherapy alone or chemoradiotherapy.[61] Those receiving chemotherapy are reassessed (including cystoscopy, examination, TURBT, and CT imaging) following 2 or 3 courses of chemotherapy. Patients receiving chemoradiotherapy are reassessed 2-3 months after treatment.[61]

If there is no response, chemoradiotherapy or a new systemic therapy regimen can be considered.

See local specialist protocol for dosing guidelines.

Primary options

ddMVAC

methotrexate

and

vinblastine

and

doxorubicin

and

cisplatin

OR

gemcitabine

and

cisplatin

Consider – radical cystectomy or consolidation chemotherapy ± radiotherapy

Back
ACUTE
|
locally invasive tumours
|
unresectable locally advanced: T4b or N2-3
Consider – 

radical cystectomy or consolidation chemotherapy ± radiotherapy

Additional treatment recommended for SOME patients in selected patient group

For patients with T1-T4a N2-3 disease, if the tumour responds to primary treatment (downstaging chemotherapy), subsequent options include cystectomy or chemoradiotherapy.[61]

For patients with T4b disease, if there is no tumour present after primary treatment (chemotherapy or chemoradiotherapy), subsequent options include consolidation chemotherapy or, if no prior radiotherapy, chemoradiotherapy.[61] Cystectomy may be an option if the tumour responds to primary treatment.[61]

Consider – maintenance avelumab

Back
ACUTE
|
locally invasive tumours
|
unresectable locally advanced: T4b or N2-3
Consider – 

maintenance avelumab

Additional treatment recommended for SOME patients in selected patient group

Maintenance avelumab is recommended following completion of chemotherapy for patients with a good response and no disease progression.[61]​​[137] In a phase 3 trial of patients with metastatic or locally advanced (unresectable) disease, maintenance avelumab increased overall survival by 7.1 months compared with supportive therapy.[138]

See local specialist protocol for dosing guidelines.

Primary options

avelumab

metastatic disease

1st line – immunotherapy and/or chemotherapy

Back
ACUTE
|
metastatic disease
1st line – 

immunotherapy and/or chemotherapy

Patients who present with metastatic disease, or subsequently develop metastatic disease, are generally treated with systemic therapy.​[50][61]

The therapy regimen used may vary according to factors such as the presence and severity of comorbidities (e.g., cardiac disease, neuropathy, hearing loss, renal dysfunction), together with an assessment of risk based on extent of disease.

Guidelines recommend pembrolizumab plus enfortumab vedotin (an antibody-drug conjugate) as the preferred first-line treatment for patients with metastatic disease who are fit enough for combination therapy.​[50][61][139]​​ Improved survival outcomes have been reported with pembrolizumab plus enfortumab vedotin compared with cisplatin-based chemotherapy.[140][141]

For patients with metastatic disease who are not able to receive pembrolizumab plus enfortumab vedotin (e.g., due to contraindications or availability), recommended regimens for cisplatin-eligible patients include dose-dense methotrexate plus vinblastine plus doxorubicin plus cisplatin (ddMVAC), or gemcitabine plus cisplatin, or gemcitabine plus cisplatin plus nivolumab.​[50][61][139][142]​ 

Gemcitabine plus carboplatin is the preferred chemotherapy regimen for these patients unable to tolerate cisplatin (i.e., those with any of: creatinine clearance <60 mL/min; Eastern Cooperative Oncology Group performance score 2; grade ≥2 neuropathy or hearing loss; New York Heart Association class III heart failure).​[50][61][139][143][144]​​

After 2 or 3 cycles of chemotherapy, patients are re-evaluated and treatment is continued for up to 6 cycles in total if the disease has responded or remained stable.[61]

Further options for first-line systemic therapy may include pembrolizumab or atezolizumab for patients ineligible for any platinum-containing chemotherapy.​[145][147]​​ Atezolizumab may be considered for patients with tumours positive for PD-L1 expression.[61][145]​ 

Subcutaneous formulations of nivolumab, pembrolizumab, and atezolizumab (nivolumab/hyaluronidase, pembrolizumab/berahyaluronidase alfa, and atezolizumab/hyaluronidase) may be substituted for intravenous formulations (dosing and administration instructions are different between the formulations).[61]

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

or

pembrolizumab/berahyaluronidase alfa

-- AND --

enfortumab vedotin

Secondary options

ddMVAC

methotrexate

and

vinblastine

and

doxorubicin

and

cisplatin

OR

gemcitabine

and

cisplatin

OR

gemcitabine

-- AND --

cisplatin

-- AND --

nivolumab

or

nivolumab/hyaluronidase

Tertiary options

gemcitabine

and

carboplatin

OR

pembrolizumab

OR

pembrolizumab/berahyaluronidase alfa

OR

atezolizumab

OR

atezolizumab/hyaluronidase

Consider – surgery or radiotherapy

Back
ACUTE
|
metastatic disease
Consider – 

surgery or radiotherapy

Additional treatment recommended for SOME patients in selected patient group

Palliative radiotherapy, usually in combination with systemic therapy, can reduce symptoms or improve local control.

Surgery or radiotherapy may be considered in highly selected patients who show a major partial response in an unresectable primary tumour or have a solitary site of residual disease that is resectable after chemotherapy.​[50][61]​​ In selected series this has been shown to afford survival benefit.[148]

If disease is completely resected, two additional cycles of chemotherapy can be given if tolerated by the patient.

Consider – maintenance avelumab or nivolumab

Back
ACUTE
|
metastatic disease
Consider – 

maintenance avelumab or nivolumab

Additional treatment recommended for SOME patients in selected patient group

​Maintenance avelumab is recommended following completion of chemotherapy (without nivolumab) for patients with good response and no disease progression.​[50][61][137][138]

For patients receiving gemcitabine and cisplatin plus nivolumab, maintenance nivolumab is recommended.​[50][61][142]

A subcutaneous formulation of nivolumab (nivolumab/hyaluronidase) may be substituted for the intravenous formulation (dosing and administration instructions are different between the formulations).[61]

See local specialist protocol for dosing guidelines.

Primary options

avelumab

OR

nivolumab

OR

nivolumab/hyaluronidase

2nd line – clinical trial or platinum-based chemotherapy or immunotherapy

Back
ACUTE
|
metastatic disease
2nd line – 

clinical trial or platinum-based chemotherapy or immunotherapy

Enrolment in a clinical trial, if eligible, is strongly recommended for second-line and subsequent-line therapies for advanced and metastatic disease; evidence for optimal treatment selection is lacking. Choice of treatment should be based on prior therapy and cisplatin eligibility.

For patients who progress following first-line treatment with pembrolizumab plus enfortumab vedotin (no prior chemotherapy), guidelines recommend platinum-based chemotherapy. If ineligible for cisplatin-based chemotherapy, gemcitabine plus carboplatin may be an option.​[50]​​​[61]

Pembrolizumab alone or with enfortumab vedotin, enfortumab vedotin alone, nivolumab, or avelumab may be used as second-line treatments in patients with metastatic disease who have disease progression during or following platinum-based chemotherapy (no prior immunotherapy or enfortumab vedotin).[61][149][150]

Enfortumab vedotin monotherapy may be considered for patients who have had previous immunotherapy with or without chemotherapy (no prior enfortumab vedotin).[61]

Subcutaneous formulations of pembrolizumab and nivolumab (pembrolizumab/berahyaluronidase alfa and nivolumab/hyaluronidase) may be substituted for intravenous formulations (dosing and administration instructions are different between the formulations).[61]

Consult a specialist for guidance on optimal treatment options for these patients.

2nd line – biomarker-based therapy

Back
ACUTE
|
metastatic disease
2nd line – 

biomarker-based therapy

​Molecular/genomic analysis, including testing for fibroblast growth factor receptor 3 (FGFR3) genetic alterations and human epidermal growth factor 2 (HER2) overexpression, may help guide subsequent treatment options and/or eligibility for clinical trials.[61]

The FGFR inhibitor erdafitinib is an alternative option for select patients with susceptible FGFR3 genetic alterations who have received at least one line of prior systemic therapy.​[50][61][139]​​​​​​[153][154]

Trastuzumab deruxtecan (a HER2-directed antibody-drug conjugate) is an option for the treatment of HER2-positive unresectable or metastatic bladder tumours in patients who have received prior treatment (or who have no further alternative treatment options).[61] In a phase 2, open-label trial, trastuzumab deruxtecan treatment resulted in an objective response rate of 39% (16/41) and a median progression-free survival of 7 months in patients with bladder cancer with HER2 overexpression (immunohistochemistry 3+/2+).[155]

See local specialist protocol for dosing guidelines.

Primary options

erdafitinib

OR

trastuzumab deruxtecan

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Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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