# Background
Urinary bladder cancer is the fourth most common cancer among men and accounts for 8% of all new male cancer cases. Urinary bladder cancer is less common among women (ranked 11th) and accounts for less than 3% of all new female cancer cases. Statistics Canada estimates that in 2022 there will be approximately 13,300 new cases of bladder cancer and 2,500 deaths associated with bladder cancer in Canada. 1 Smoking is estimated to account for between 34% and 50% of all bladder cancers. 2,3 There are several histological types of bladder cancer. Urothelial carcinoma (also known as transitional cell carcinoma, henceforth referred to as urothelial) is the most common subtype, accounting for more than 90% of all cases in North America. Other histologic variants include squamous differentiation, glandular differentiation, nested pattern, microcystic, micropapillary, lymphoepithelioma-like, plasmacytoid and lymphoma-like, sarcomatoid/carcinosarcoma, giant cell, trophoblastic differentiation, clear cell, lipid cell, and undifferentiated. 4 Other important histologic variants include adenocarcinoma (urachal and non-urachal) and small cell carcinoma. Less commonly, urothelial cancers can arise in other parts of the urinary tract including the renal pelvis, ureter and urethra.
Staging of bladder cancer is currently based on the eighth edition (2017) of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. 5 One of the major updates from the seventh edition (2010) is that lymph node involvement limited to the true pelvis and/or common iliac lymph nodes (N1-N3) in combination with a T1-T4a primary tumour now constitutes stage III disease (previously stage IV). A detailed description of the staging system can be found in the Appendix.
The objective of this guideline is to provide physicians with the latest, evidence-based management strategies for locally advanced/metastatic bladder cancer in Alberta. Guidelines for non-muscleinvasive bladder cancer, muscle-invasive bladder cancer, and upper tract urothelial cancer are available separately. 

# Target Population
The target population for this guideline is adult patients (18 years of age or older) with a diagnosis of locally advanced/metastatic bladder cancer (i.e. T4bNxM0, TxN2-3M0, TxNxM1).

# Recommendations

# Management of Locally Advanced Disease (Stages T4bNxM0, TxN2-3M0)
Indications include pre-operatively identified direct pelvic/abdominal wall invasion (cT4b), multiple regional lymph node metastases in the true pelvis (cN2), or lymph node metastases to common iliac lymph nodes (cN3). For post-operatively identified pT4b or pN1-3 disease, please see Muscle-Invasive Bladder Cancer AHS Guidelines for recommendations re: adjuvant therapy. - Carboplatin-gemcitabine (21-day cycle): carboplatin AUC5 day 1, gemcitabine 1000 mg/m 2 days 1 and 8 D. For patients who have a favourable response to first-line chemotherapy, consideration of consolidative definitive loco-regional treatment (i.e. cystectomy with pelvic lymphadenectomy or bladder-preserving trimodality therapy) should be considered in the multidisciplinary setting. E. Patients who do not have a favourable response to first-line chemotherapy and/or are not candidates for local definitive consolidative therapy should be managed as per recommendations for metastatic disease (see below). F. Patients who are ineligible for aggressive multi-agent chemotherapy may be treated with single modality therapy, i.e. single-agent chemotherapy or radiotherapy for palliation and/or survival prolongation.

# Palliative local therapies
A. Palliative local therapies (i.e. TURBT, cystectomy, radiation) may be considered for patients experiencing intolerable pain/voiding symptoms or recurrent/refractory hematuria.

# Follow-up A.
In patients with favourable response to first-line chemotherapy who undergo subsequent consolidative curative-intent locoregional therapy (i.e. surgical resection versus bladder-preserving trimodality therapy), follow up should be performed as outlined in the Muscle-Invasive Bladder Cancer AHS Guidelines. B. In patients who do not undergo curative intent locoregional therapy, follow up should be performed as outlined for Metastatic Bladder Cancer (see below).

# Management of Metastatic Disease (TxNxM1)
Indications include the development of recurrent/metastatic disease post radical therapy or presentation with de novo metastatic disease. E. CBC and diff, electrolytes, creatinine, calcium, magnesium, liver panel within 2 weeks of starting chemotherapy. All patients starting systemic chemotherapy should be considered for HBV screening. i. Carboplatin-gemcitabine (21-day cycle): carboplatin AUC5 day 1, gemcitabine 1000 mg/m 2 days 1 and 8 H. For patients who are ineligible for any of the above systemic treatment options, alternative regimens that may be considered include: gemcitabine-paclitaxel, single-agent gemcitabine, single-agent paclitaxel. I. For patients who are chemotherapy-ineligible, best supportive care is recommended.

# First-line

# Maintenance therapy:
A. For patients who do not progress (ie: have stable disease, a partial response, or complete response) after 4-6 cycles of platinum-based 1 st line chemotherapy, maintenance immunotherapy with avelumab is recommended. Standard dosing is provided below:
i. Avelumab (14-day cycle): The recommended dose is 10 mg/kg body weight administered IV over 60 minutes every 2 weeks. ii. Avelumab is to be started 4-10 weeks after the last dose of chemotherapy.
iii. Avelumab is continued until disease progression or unacceptable toxicity.

# Second-line therapy:
A. In eligible patients, pembrolizumab should be considered for patients who progress on or after 1 st line platinum-based chemotherapy, or in those who have recurred/progressed within 12 months of receiving platinum-based chemotherapy in the (neo)adjuvant setting. 6 Standard dosing of pembrolizumab is as follows: i. Pembrolizumab (21-day cycle): 2mg/kg up to maximum of 200 mg IV day 1 B. Retreatment with platinum-based regimens can be considered if initial progression-free interval to platinum was > 12 months. C. Pembrolizumab is NOT indicated for patients who have progressed on avelumab maintenance therapy. D. For patients who received immunotherapy alone in the first-line setting as part of a clinical trial, platinum-based chemotherapy is recommended as per first-line therapy above if the patient is eligible and has not previously received platinum-based treatment. If prior platinum-based therapy has been received (with <12 month treatment-free interval) and/or the patient is ineligible, secondline options are as per third-line therapy and beyond (see below).

# Third-line therapy:
A. Enfortumab Vedotin is a nectin-4 directed antibody microtubule inhibitor drug conjugate. It is recommended for eligible patients who have progressed after platinum-based 1 st line chemotherapy and immunotherapy (maintenance or 2 nd line). Standard dosing is provided below: i. Enfortumab vedotin (28-day cycle): 1.25mg/kg IV day 1, day 8, day 15 ii. Enfortumab vedotin is continued until disease progression or unacceptable toxicity iii. Enfortumab vedotin is pending Health Canada approval and provincial funding. At time of writing, it is currently available via special access program. This agent has novel toxicities which require monitoring and evaluation. Please refer to the product monograph. Product monograph link here. B. Erdafitinib is a treatment option in patients with selected FGFR mutations and fusions. The phase II BLC 2001 study enrolled patients with advanced urothelial carcinoma with prespecified FGFR alterations demonstrating a ORR of 40%. Patients had all been previously treated with platinum-based chemotherapy and some with immunotherapy. Erdafitinib is currently Health Canada approved and is available via a patient access program, pending provincial approval and funding i. This agent has novel toxicities which require monitoring and evaluation. For dosing and toxicity information, please refer to the product monograph. Product monograph link here.
ii. Currently there is no level I evidence to guide sequencing of therapies after 1 st -line chemotherapy in patients with FGFR mutations and fusions.

# Fourth-line therapy and beyond:
A. Taxane-based chemotherapy can be considered post-progression on platinum-based chemotherapy and immunotherapy and enfortumab vedotin. Commonly used agents are singleagent paclitaxel or docetaxel.

# Palliative local therapies
A. Palliative local therapies (i.e. TURBT, cystectomy, radiation) may be considered for patients experiencing intolerable pain/voiding symptoms or recurrent/refractory hematuria. B. RT or surgery should be considered in patients with symptomatic sites of bony metastases and/or with impending fracture/complication.

# Follow-up
A. Post-chemotherapy: clinical evaluation and imaging (e.g. CT chest, abdomen, pelvis) to evaluate tumour response and then as indicated (q3months is a reasonable interval for most patients). B. Consider early palliative care referral as indicated.

# Special situations
A. Non-urothelial histology i. All pathology reported to have variant histology should be reviewed by an expert GU pathologist.
ii. All patients with pure non-urothelial histology should be discussed in a multidisciplinary setting.
iii. Generally, platinum-based chemotherapy as recommended for metastatic urothelial carcinomas are felt to less effective for pure non-urothelial histologies. However, there are no high-quality data to recommend alternate systemic therapy options for this population. iv. For urachal or non-urachal bladder adenocarcinoma, it is reasonable to consider systemic therapy options similar to those used in the management of metastatic colorectal cancer (e.g. FOLFOX). 7,8 Cisplatin-5FU is another reasonable option. v. For metastatic squamous cell carcinoma of the bladder, standard urothelial cisplatin-based regimens are appropriate. It is also reasonable to consider 5-FU or taxane-based chemotherapy. vi. For metastatic small cell carcinoma of the bladder, first-line treatment should consist of platinum-etoposide combination chemotherapy in all eligible patients. Guidelines for management of metastatic small cell carcinoma of the lung should be followed.

# Discussion

# Management of Locally Advanced Disease (T4b and/or N2-3, M0)
In patients with locally advanced disease (T4b and/or N2-3, M0), recommended first-line therapy is systemic platinum-based chemotherapy for those that are eligible. Subsequent disease management depends on the response to primary systemic chemotherapy.
A retrospective study of 659 patients with node-positive urothelial bladder cancer assessed the effectiveness of induction chemotherapy for downstaging. 6 Amongst patients with cN2-3 disease, the rate of pathologic complete downstaging was 27% in those receiving induction treatment. Patients who exhibit substantial downstaging should be considered for consolidation definitive loco-regional therapy. 3-year OS rates for patients receiving induction chemotherapy followed by radical cystectomy have been reported to be 43% in patients with cN2-3 disease, with 3-year OS rates >80% in those achieving pathologic complete downstaging prior to surgery.
Patients who do not have a favourable response to first-line chemotherapy and/or are not candidates for loco-regional definitive consolidative therapy should be managed as per recommendations for metastatic disease (see below).

# Management of Recurrent or Metastatic Disease (Tx, Nx, M1)
Recurrent or metastatic disease should be treated primarily with systemic chemotherapy. A cisplatinbased regimen is the preferred initial therapy for patients with metastatic urothelial cancer for patients who are eligible. Eligible patients are defined as those who do not have one of the following criteria: CrCl <60 ml/min, PS  2, NYHA  3 heart failure,  Grade 2 peripheral neuropathy,  Grade 2 hearing loss. 7 All patients with impaired renal function with a potential reversible cause (e.g. obstructive uropathy due to tumour), should be considered for treatment measures to improve renal function prior to initiation of platinum-based therapy.
Recommended cisplatin-based first-line therapies include cisplatin-gemcitabine and dose-dense MVAC. A randomized, phase III RCT compared cisplatin-gemcitabine to conventionally dosed MVAC in 405 patients and demonstrated no significant differences in response rate (49% vs 46%) or overall survival (HR 1.04, p=0.75). However, cisplatin-gemcitabine was better tolerated with lower rates of side effects including neutropenia, febrile neutropenia, and mucositis. 8 Dose-dense MVAC was also shown to have similar efficacy as conventionally dosed MVAC, with a reduction in toxicity (N=263). 9 Given the data from these 2 landmark trials, conventionally dosed MVAC is no longer recommended.
In general, triplet combination chemotherapy with paclitaxel, gemcitabine and cisplatin is not recommended due to an increase in toxicity with no significant differences in PFS or OS. 10 For patients who are not candidates for cisplatin, carboplatin may be substituted in the recurrent/metastatic setting.  For platinum-ineligible patients, first-line immunotherapy with pembrolizumab is Health Canada approved. This is based on the KEYNOTE-052 single-arm phase II study that demonstrated a response rate of 29% (7% CR, 22% PR) with pembrolizumab as first-line therapy in platinumineligible patients. 15 Patients may be able to access pembrolizumab for this indication through patient support programs.
Maintenance avelumab is recommended for patients who have stable disease or a response to 1 stline platinum based chemotherapy. In a randomized phase III trial (JAVELIN Bladder 100), 16  Erdafitinib is currently under investigation in the phase III setting (NCT03390504), however, phase II data has shown great promise in locally advanced and uresectable or metastatic urothelial carcinoma patients with prespecified FGFR alterations. In the trial all patients had disease progression after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy (prior immunotherapy was allowed). A total of n=99 patients were evaluated in an open-label, phase 2 design. The rate of confirmed response to erdafitinib therapy was 40% (3% complete response, 37% partial response). Among n=22 patients who underwent previous immunotherapy, the confirmed response rate was 59%. The median duration for progression-free survival was 5.5 months, and the median duration for overall survival was 13.8 months. Grade 3 or higher adverse events were managed mainly by dose adjustments, and 13% of patients discontinued treatment because of adverse event. 18 Enfortumab Vedotin was evaluated in a phase III clinical trial (EV-301) 19 of 608 patients with locally advanced unresectable or metastatic urothelial carcinoma (including those with squamous differentiation or mixed cell types) previously treated with platinum-based chemotherapy and PD-1/PD-L1 inhibitor. Patients were randomly assigned to either enfortumab vedotin or investigator's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). At median follow-up of approximately 11 months, compared with chemotherapy, enfortumab vedotin improved OS (median 13 versus 9 months, HR 0.70, 95% CI 0.56-0.89), PFS (median 6 versus 4 months, HR 0.62, 95% CI 0.51-0.75) and overall response rates (41 versus 18 percent).Grade 3 toxicity rates for any adverse event were similar between the two treatment arms (51 versus 50 percent). Grade 3 toxicities specifically associated with enfortumab vedotin included rash (15 percent), peripheral neuropathy (5 percent), and hyperglycemia (4 percent). Ocular toxicities, pneumonitis (eg, interstitial lung disease), and severe cutaneous adverse reactions, including cases of Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have also been reported with this agent. This is currently pending Health Canada review and is currently available via special access program.

# Appendix A: Cancer Staging

# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including surgical oncologists, radiation oncologists, medical oncologists, urologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020.

# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.

# Abbreviations
AHS, Alberta Health Services; AJCC, American Joint Committee on Cancer; CCA, Cancer Care Alberta; MVAC, Methotrexate, vinblastine sulfate, doxorubicin hydrochloride; TURBT, Transurethral resection of a bladder tumor.