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BLADDER CANCER: UNRESECTABLE LOCALLY ADVANCED & METASTATIC

Includes 2019 CUA Consensus Statement on Management of cT4b and / or cN1-3 urothelial carcinoma of the bladder

Metastatic bladder cancer

Most common sites of metastasis: bone, liver, lung
Non-local regional recurrences after radical cystectomy for localized disease are reflective of the presence of micrometastatic disease at the time of diagnosis and treatment

2019 Consensus Statement on Management of locally advanced and metastatic urothelial carcinoma of the bladder

In this consensus statement, locally advanced bladder cancer is defined as cT4b and / or cN1-3.

Clinical T4b disease (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):
1. eGFR ≤ 60 ml/min/1.73m2
2. Heart failure (NYHA Class > II)
3. ≥Grade 2 hearing loss (grading based on Common Terminology Criteria for Adverse Events version 4.0)
4. ≥Grade 2 neuropathy (grading based on Common Terminology Criteria for Adverse Events version 4.0)
5. 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, GC was compared to the earlier standard of MVAC. GC demonstrated similar efficacy but with reduced toxicity.
Dose dense(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

Checkpoint inhibitors active on the PD-1/PD-L1 interaction between tumour cells and cytotoxic T cells, such as pembrolizumab and atezolizumab, have demonstrated efficacy in a first line setting in cisplatin-ineligible patients with advanced UC.
KEYNOTE-361 (not included in 2019 CUA guidelines)
- Objective: evaluate pembrolizumab as first-line treatment for previously untreated locally advanced, unresectable, or metastatic urothelial carcinoma
- Population: ≈1000 patients with previously untreated locally advanced, unresectable, or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra
  - Primary tumour site is in lower tract for majority of patients (≈80%)
- Randomized to intravenous pembrolizumab + chemotherapy (gemcitabine + cisplatin or gemcitabine + carboplatin) vs. pembrolizumab alone vs. chemotherapy alone
- Primary outcome: dual primary endpoints of progression-free survival and overall survival
- Results:
  - Median follow-up 31.7 months
  - No significant difference in progression-free or overall survival with combination pembrolizumab + chemotherapy vs. chemotherapy alone
  - No significant difference in overall survival with pembrolizumab alone vs. chemotherapy alone
- Interpretation: compared to chemotherapy alone, combination pembrolizumab + chemotherapy does not significantly improve survival in patients with previously untreated locally advanced, unresectable, or metastatic urothelial carcinoma
- Powles, Thomas, et al."Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial." The Lancet Oncology (2021).
2019 CUA Guidelines: not routinely recommended in the first line setting for cisplatin-ineligible patients
FDA
- In August 2021, pembrolizumab received FDA approval for patients with previously untreated locally advanced, unresectable, or metastatic urothelial carcinoma that are inelgible for any platinum-containing chemotherapy

Second-line systemic therapy:

Although the majority (40-70%) of patients with metastatic disease will experience an initial response to chemotherapy, most will ultimately progress with a median survival of 14 months and overall 5-year survival rates of 5-20%. Patients who fail first-line chemotherapy have a dismal prognosis
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, there was no standout salvage chemotherapy regimen for patients with unresectable locally advanced and metastatic UC 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 the 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

CheckMate 275

Nivolumab

JAVELIN§

Avelumab

Durvalumab§

In the second line setting PD-L1 testing by immunohistochemistry should not be used to select patients for immunotherapy

In some, but not all studies, PD-L1 positivity has been associated with a higher objective response rate. In the second line setting, however, findings from both the Keynote 045 and IMvigor trials suggest that the benefit of checkpoint inhibitors is not limited to those with PD-L1-positive tumours
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

Cancers of the ureter, renal pelvis and proximal urethra constitute approximately 5-10% of cases of urothelial carcinoma and are treated with similar systemic therapy as bladder cancer

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

Current (as of consensus statement publication) 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 systemic 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:

Persistent N3 disease after initial chemotherapy, where the risk of relapse is high and radiotherapy represents a less invasive treatment option
cT4b disease that fails to obtain down staging with initial chemotherapy, where surgery is usually not feasible

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.

Questions

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 94