Editing CUA: Advanced and Metastatic Urothelial Cancer (2019) (section)

===== '''Management of cT4b and / or cN1-3 urothelial carcinoma of the bladder''' =====

* '''In UC of the bladder, clinical T4b disease is defined as a tumour which invades the pelvic wall, abdominal wall or adjacent bowel / rectus is considered unresectable unless significant downstaging can be achieved. Clinical N1-2 disease consists of lymph node involvement in the true pelvis, whereas N3 consists of common iliac lymph node involvement.'''
* Patients with cT4b or N1-3 urothelial carcinoma of the bladder should be discussed in a multidisciplinary forum including an experienced Urologist / Uro-Oncologist and Radiation Oncologist.
* Patients with cT4b and / or cN1-3 urothelial carcinoma of the bladder can be cured using multi-modality treatment.
** A further argument for a curative treatment approach is the potential for inaccurate clinical staging of lymph nodes. In studies of patients with cN1-3 who have proceeded directly to surgery a proportion have had pN0 disease implying false positive clinical staging
* '''UrologySchool.com Summary'''
** '''First-line: 4-6 cycles of gemcitabine + cisplatin'''
*** '''If cisplatin contraindicated, then gemcitabine + carboplatin'''
*** '''If not suitable for combination, single agent gemcitabine, paclitaxel or docetaxel (NO immunotherapy)'''
** '''Second-line: pembrolizumab'''
* '''First-line systemic therapy'''
** '''In suitable patients, the preferred approach is to commence systemic chemotherapy with 4 – 6 cycles of platinum-based chemotherapy'''
*** '''CUA contraindications to cisplatin-based chemotherapy (5, almost identical to NAC contraindications except for eGFR cut-off (recall cut-off ≤ 50 for NAC):'''
***# '''eGFR ≤ 60''' ml/min/1.73m2
***# '''Heart failure (NYHA Class > II)'''
***# '''≥Grade 2 hearing loss''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
***# '''≥Grade 2 neuropathy''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
***# '''Eastern Cooperative Group (ECOG) ≥2'''
*** '''In select cases, eligibility criteria may be extended to patients with eGFR of 45 - 60mls/min and / or ECOG 2 performance status. Administering split dose cisplatin is an option for these patients'''.
*** '''In patients suitable for cisplatin-based chemotherapy, the preferred routine regimen is GC.'''
**** In a phase III randomized trial, gemcitabine/cisplatin was compared to the earlier standard of methotrexate, vinblastine, doxorubicin and cyclophosphamide (MVAC). GC demonstrated similar efficacy but with reduced toxicity.
**** '''Dose dense methotrexate, vinblastine, doxorubicin and cyclophosphamide (DD-MVAC) with growth factor support may be considered in select cases where a more aggressive treatment approach is being considered.'''
***** EORTC 30924
****** Randomized patients to two weekly MVAC (DD-MVAC) with growth factor to standard MVAC.
****** 5 year OS improved significantly in DD-MVAC (21.8% DD-MVAC vs. 13.5% standard MVAC)
**** '''Currently, there are no completed clinical trials supporting the use of first line immunotherapy in cisplatin eligible patients. However, numerous trials are currently evaluating the role of first line immunotherapy.'''
*** '''In patients ineligible for cisplatin-based chemotherapy, the preferred regimen is gemcitabine/carboplatin (GCa)'''
**** Carboplatin based regimens are inferior to cisplatin-based regimens with lower response rates and trend towards inferior survival. Nonetheless, carboplatin is active in urothelial carcinoma and is the cornerstone of preferred regimens in cisplatin-ineligible patients.
**** '''In patients not suitable for combination chemotherapy, single agent gemcitabine, paclitaxel or docetaxel is recommended.'''
***** In patients not suitable for combination therapy, single agent gemcitabine, paclitaxel or docetaxel has been studied in small single arm phase II studies. Response rates have varied between 25 – 47% but have generally been of short duration with median OS ranging between 8 – 12 months in these series.
**** '''Immunotherapy is not routinely recommended in the first line setting for cisplatin-ineligible patients'''
***** Checkpoint inhibitors active on the PD-1 / PD-L1 interaction between tumour cells and cytotoxic T cells, have demonstrated efficacy in a first line setting in cisplatin-ineligible patients with advanced UC.
****** Phase II studies utilizing immunotherapy as first line treatment in cisplatin-ineligible patients with advanced UC have evaluated pembrolizumab, a monoclonal antibody against the PD-1 receptor on T cells and other immune cells, and atezolizumab, a monoclonal antibody against the PD-L1 receptor on tumour and immune cells
** '''Second-line systemic therapy:'''
*** '''In patients who have progressive disease during or after platinum-based chemotherapy, pembrolizumab is the preferred regimen (if available)'''
**** Prior to the advent of checkpoint inhibitors in unresectable locally advanced and metastatic UC, there was no standout salvage chemotherapy regimen for patients progressing during or after platinum-based regimens
**** The evidence supporting the use of checkpoint inhibitors in the second line setting is more robust than in the first line setting. As of publication of consensus statement, 5 checkpoint inhibitors have been tested in this setting including 2 in randomized phase III studies.
***** '''Keynote 045'''
****** Randomized 542 patients with progressive disease during or after platinum based chemotherapy to pembrolizumab vs. investigators’ choice of single agent paclitaxel, docetaxel or vinflunine
****** Median OS was 10.3 months with pembrolizumab compared to 7.4 months on chemotherapy.
****** Grade 3 – 5 toxicity was seen in 15% of patients on pembrolizumab compared to 49% on chemotherapy.
***** '''IMvigor 211'''
****** Randomized patients to atezolizumab vs. investigators’ choice of paclitaxel, docetaxel or vinflunine
**** '''The role of PD-L1 testing in selecting patients for immunotherapy'''
***** In the second line setting, findings from both the Keynote 045 and IMvigor 211 randomized phase III studies suggest that benefit of checkpoint inhibitors is not limited to those with PD-L1-positive tumours by IHC.
***** In some, but not all studies, PD-L1 positivity has been associated with a higher ORR.
***** '''In the second line setting PD-L1 testing by immunohistochemistry should not be used to select patients for immunotherapy'''
***** To date no single biomarker has been able to predict response to immune-oncologic (I-O) therapies in urothelial carcinoma.
*** '''Where pembrolizumab is unavailable or a patient is ineligible, single agent paclitaxel or docetaxel is preferred for the majority of patients.'''
*** '''Re-treatment with a platinum based regimen is a reasonable option in a patient who has disease progression following a prolonged (> 6 – 12 month) initial response to platinum-based chemotherapy.'''
**** Patients progressing within 6-12 months of initial platinum-based chemotherapy are likely to be refractory to further platinum therapy.

** '''Current approvals and the status of the evidence of immunotherapy in advanced urothelial carcinoma'''
*** In the first line setting, neither pembrolizumab nor atezolizumab has been approved by Health Canada (Health Canada, 2018). Both agents received accelerated approval by both the FDA for cisplatin-ineligible patients, and are endorsed by NCCN in this population. Recently the indication has been narrowed to those patients whose tumours are PD-L1 positive, or who are not eligible for any platinum chemotherapy regardless of PD-L1 expression. An application for first line pembrolizumab along similar lines to FDA  approval has been made to the Pan-Canadian Oncology Drug Review (pCODR).
*** In the second line setting, pembrolizumab, atezolizumab, durvalumab and avelumab have been approved by Health Canada for use in patients progressing during or following platinum-based chemotherapy or those who relapse within 12 months of receiving neoadjuvant or adjuvant platinum based chemotherapy for earlier stage disease

{| class="wikitable"
| colspan="4" |'''Current phase 3 studies of immunotherapy in locally advanced and metastatic urothelial carcinoma'''
|-
|'''Study'''
|'''Disease state'''
|'''Treatment arms'''
|'''Estimated completion date'''
|-
|'''Imvigor 130'''
|1st line
|Atezolizumab vs. Atezolizumab/platinum based chemotherapy vs. platinum based chemotherapy
|November 2020
|-
|'''Keynote 361'''
|1st line
|Pembrolizumab vs. Pembrolizumab/platinum based chemotherapy vs. platinum based chemotherapy
|May 2020
|-
|'''Danube'''
|1st line
|Durvalumab + tremelimumab vs durvalumab vs. standard chemotherapy
|September 2019
|-
|'''Javelin Bladder 100'''
|Maintenance following 1st line
|Avelumab + BSC vs. BSC alone
|July 2020
|-
|'''Checkmate 901'''
|1st line
|Nivolumab/ipilimumab vs. platinum-based chemotherapy

Nivolumab/cisplatin gemcitabine vs. cisplatin gemcitabine alone
|December 2022
|}

* '''Consolidation treatment after systemtic therapy'''
** '''Depending on response to initial chemotherapy, consolidation with either RC + pelvic lymph node dissection (PLND) or radical radiotherapy (+/- concurrent chemotherapy) can be administered.'''
*** The choice of consolidative treatment is best made on an individual basis with multidisciplinary input. There are 2 situations which would favour radiotherapy as opposed to surgery:
**** A patient with persistent N3 disease after IC, where the risk of relapse is high and radiotherapy represents a less invasive treatment option
**** A patient with cT4b disease who fails to obtain down staging with IC, where surgery is usually not feasible
* '''The role of aggressive surgical / radiotherapeutic management in oligometastastic disease.'''
** In patients with oligometastatic or limited metastatic disease, routine practice of metastasectomy treatment to metastatic disease is not recommended. However, such treatment may be appropriate in selected cases.
*** The targeting of oligometastatic disease with surgical resection and / or ablative radiotherapy has only been tested in small series of highly selected patients with no randomized studies to guide practice.
*** The decision to treat oligometastatic disease with local therapies should be made in a multidisciplinary context with involvement of an experienced medical oncologist, uro-oncologist and radiation oncologist where appropriate
** In patients with metastatic UC of the bladder, routine practice of localized treatment (RC or HDRT (+/- chemotherapy)) to the primary is not recommended. However, such treatment may be appropriate in selected cases
** Individualization of local treatment following systemic treatment is the most judicious approach. The aggressiveness of the local treatment will vary according to the initial local stage and the subsequent local and systemic response to the chemotherapy.