Core Outcome Measures in Effectiveness Trials

Bladder Cancer Core Outcome Sets (B-COS) programme encompassing 1) non-muscle-invasive bladder cancer 2) muscle invasive bladder cancer and 3) metastatic bladder cancer

General Information

Summary:
Background
Bladder cancer is the 7th commonest male, and 17th commonest cancer in women. It is split in two broad categories, non-muscle invasive (NMIBC) and muscle-invasive (MIBC) bladder cancer, the latter having a higher risk of death. Most cases (75-85%) present as NMIBC and these patients typically have a higher long-term survival and lower cancer specific mortality compared to those with MIBC. Tobacco smoke is considered the most common risk factor and other factors such as occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons have been identified.

NMIBC
NMIBC is defined as tumour(s) confined to the mucosa or invading the lamina propria. Using the TNM staging system they are classified as Ta-T1 or Tis N0 M0. NMIBC tumours may be graded using the WHO 1973 or WHO 2004 grading systems – both indicating worse prognosis with increasing grade. Diagnosis ultimately depends on cystoscopy, biopsy and the pathology report.
NMIBC is initially treated conservatively (sparing the bladder) with curative intent by a Transurethral Resection of the Bladder Tumour (TURBT) during which tumour(s) are surgically excised. NMIBC recurrences are frequent (30-80% within 5 years) and up to 45% progress to MIBC within 5 years. Consequently, NMIBC is seen as a chronic disease requiring frequent follow-up and repeated TURBTs making it the most expensive of all cancers to treat from diagnosis to death with additional productivity losses and informal care costs.

MIBC
Diagnosis of MIBC is also made via cystoscopy and pathology reports. MIBC involves larger tumours (T2-T4) which have invaded the bladder muscle (T2a – T2b) or beyond and in to the perivesical tissue (T3a-T3b) or invading the prostate stroma, seminal vesicles, uterus, vagina, pelvic wall or abdominal wall (T4a-T4b). The same grading systems as used for NIMBC are used, but in MIBC all tumours are high grade. CT and/or MRI are used to provide further staging information regarding extent of tumour invasion, assess lymph node invasion, and to detect metastases.
For some localised MIBC tumours a TURBT may be attempted in cases where the whole tumour can be resected, and external beam radiotherapy (EBRT) has been described. However, Radical cystectomy (RC) (removal of the bladder) with lymph node dissection (LND) is considered the optimal curative approach in patients with non-metastatic MIBC. Pelvic organ sparing approaches, aimed at preserving functional control, and various urinary diversions have also been described but no high quality evidence of effectiveness is available.

Metastatic bladder cancer
Metastatic disease involves patients whose cancer has spread regionally in the lymph nodes (=N1) or spread to non-regional lymph nodes or other distant sites (=M1). Metastatic bladder cancer is usually treated first-line with single or combination therapeutic agents depending on fitness. Immunotherapy is an option for patients who have progressed during previous chemotherapy or are unfit for chemotherapy, but the level of evidence supporting its use is not yet accumulated to high level of evidence with strong recommendations.

Why is it important to develop core outcome sets for bladder cancer?
Heterogeneous outcome reporting in bladder cancer trials has been reported in recent systematic reviews of intervention effectiveness. This situation hinders comparing and contrasting the results of individual trials as well as critical reviews of the evidence base, and is open to the potential for selective outcome reporting bias. The knock-on effect is that making evidence based recommendations in guideline panels, and decision-making by clinicians and patients, is hampered.
Developing a core outcome set (COS) is a solution to reduce outcome heterogeneity, selective outcome reporting and ensures that all trials contribute useable information to the evidence base. A COS is an agreed standardised collection of outcomes which should be measured and reported, as a minimum, in all trials for a specific clinical area.
To address outcome heterogeneity we have initiated a collaboration to develop Bladder cancer Core Outcome Sets (B-COS). The features of the disease, and the various treatments available for each stage, dictate that it is most likely that there is a need for 3 COS aligning with the 3 broad categories of disease: NMIBC, MIBC and metastatic bladder cancer. The scope of each COS is detailed further below.

Scope of the NMIBC COS
Population
• Adult (=8 years) males and females with histologically confirmed urothelial NMIBC, stage Ta or T1 N0 M0, with or without carcinoma in situ (CIS), and any grade of tumour (using any grading system)
Interventions
• All intravesical adjuvant prophylactic treatments after TURBT
Comparators
• TURBT alone, placebo or any listed intervention

Scope of the MIBC COS
Population
• Adult (=18 years) males and females with histologically confirmed urothelial MIBC, stage T2-T4 N0 M0, with or without carcinoma in situ (CIS), and any grade of tumour (using any grading system)
Interventions
• Neoadjuvant chemotherapy
• Preoperative radiotherapy
• Post-operative radiotherapy
• Pelvic organ sparing radical cystectomy (including prostate-sparing, prostate capsule– sparing, seminal-sparing, and nerve-sparing in men; and preserving the neurovascular bundle, vagina, uterus, or other variations in women)
• Laparoscopic radical cystectomy
• Robot assisted radical cystectomy
• Adjuvant chemotherapy
• Extended lymph node dissection
• Urinary diversion after radical cystectomy (any type, e.g. ureterocutaneostomy, ileal or colonic conduit, continent pouches)
• Multimodality treatment (MMT) combining surgical resection, radiotherapy and chemotherapy
Comparator
Radical cystectomy or any other listed intervention

Scope of the metastatic bladder cancer COS
• Adult (=18 years) males and females with histologically confirmed urothelial bladder cancer stage T any N+ M+.
Interventions
• Chemotherapy
• Immunotherapy
Comparator
• Any intervention vs intervention or intra-intervention comparison


Contributors:
Steven MacLennan (PI) Academic Urology Unit, University of Aberdeen, UK, and the European Association of Urology Methods Committee.

Mieke van Hemelrijk. Translational Oncology and Urology Research Group, Kings College London, London, UK.

Richard T Bryan. The Institute of Cancer & Genomic Sciences University of Birmingham, Birmingham, UK.

Fredrik Leidberg. Urothelial Cancer Research Group, University of Lund, Malmo, Sweden

James N'Dow. Academic Urology Unit, University of Aberdeen, Aberdeen, UK, and the European Association of Urology Guidelines Office.

Marko Babjuk. Urology Clinic, Charles University, Prague, Czech Republic, and European Association of Urology NMIBC guidelines panel.

Fred Witjes. Faculty of Medical Sciences, Radboud University, Nijmegen, the Netherlands, and the European Association of Urology MIBC guidelines panel.

Richard Sylvester. The European Association of Urology Guidelines Office and Methods Committee

Muhammad Imran Omar. Academic Urology Unit, University of Aberdeen, UK, and the European Association of Urology Guidelines Office

Philipp Dahm. Department of Urology, University of Minnesota, and Co-ordinating Editor, Cochrane Urology


Further Study Information

Current Stage:
Ongoing
Date:
April 2018 - April 2022
Funding source(s):
None

Health Area

Disease Category
Urology

Disease Name
Bladder cancer

Target Population

Age Range
18 - 100

Sex
Either


Nature / type of Intervention
Any

Method(s)

Consensus meeting
Delphi process
Interview
Literature review
Systematic review

The methods for each of the three COS will follow broadly the same process.

1. Systematic reviews of RCTs included in relevant clinical practice guidelines and/or systematic reviews of intervention effectiveness (one each and separately for NMIBC, MIBC and metastatic disease).

2. Systematic reviews of qualitative studies reporting on the experiences of bladder cancer patients OR primary qualitative interview studies (one each and separately for NMIBC, MIBC and metastatic disease).

3. Delphi surveys involving urologists, oncologists, cancer specialist nurses (grouped as health care professionals) and bladder cancer patients who have received treatment to score the importance of each outcome (one each and separately for NMIBC, MIBC and metastatic disease).

4. Consensus meetings with representatives from each stakeholder group to discuss and vote on unclear results from the Delphi and to ratify the COS (one each and separately for NMIBC, MIBC and metastatic disease).

5. Assess the psychometric properties of each outcome in each of the NMIBC, MIBC and metastatic bladder cancer COSs

6. Where there is no clear optimal measurement, Delphi surveys involving urologists, oncologists methodologists and trialists involved in bladder cancer intervention effectiveness trials, and where appropriate patients who have received treatment for bladder cancer to score the appropriateness and feasibility of the available measurement instruments.


Stakeholders Involved

Charities
Clinical experts
Consumers (patients)
Methodologists
Patient/ support group representatives
Researchers

Study Type

COS for clinical trials or clinical research
COS for practice
Recommended outcome measures (measurement)

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