Diagnostic performance of biomarkers for bladder cancer suitable for primary care: a systematic review

Start Date May 2021

Code C16-C

Status Ongoing

Project Lead

Dr Valerie Sills and Dr Yin Zhou

Senior Lead

Prof Fiona Walter

Institution

University of Cambridge and University of Leeds

Others

Dr Evie Papavasiliou, Dr Natalia Calanzani, Dr Hannah Harrison, Dr Claudia Snudden, Prof Grant D Stewart (all Cambridge), Dr Erica di Martino (Leeds), Prof Matthew Thompson (Washington), Ms Jennifer Bovaird (PPI)

Introduction

Bladder cancer is the 11^th most common cancer in the United Kingdom. Early-stage diagnosis is associated with better survival rates. Given that the majority of bladder cancers are diagnosed following a referral (urgent or non-urgent) from a general practitioner in the UK, timely referral of suspected cases is paramount. However, diagnosis also poses challenges, as a significant proportion of bladder cancer patients do not present with visible haematuria, which is the only alarm symptom that is easily recognisable and detectable by patients and clinicians.

Although a screening program (or programs) for individuals with a high risk of developing bladder cancer could increase early-stage detection and potentially reduce mortality, these are still in early development. Furthermore, evidence suggests that there is scope to improve timely diagnosis and reduce missed diagnostic opportunities in symptomatic patients who are subsequently diagnosed with bladder cancer.

Novel urinary biomarkers have been developed in the recent years to aid the diagnosis of urinary tract cancer, in particular, bladder cancer. These have largely been developed and tested in patients who have been referred for further investigation for suspected urological cancer, but evidence on their diagnostic performance for both detecting and ruling out urinary tract cancer especially in the general population, is limited.

Against this background, we set out to systematically review the evidence of all biomarkers (individual and in panels/combinations) in the literature which have been evaluated for the diagnosis of bladder cancer. This review will be an update of previous similar reviews of specific biomarkers as well as those examining a wider range of urinary biomarkers.

Aims & objectives

We aim to update the evidence on the diagnostic performance of existing biomarkers for bladder cancer (urinary and others) across different population groups. To address our review question, we will:

Examine and describe the clinical utility of validated biomarkers for the detection of bladder cancer in the populations in which they were studied;
Ascertain the potential clinical utility and relevance of these biomarkers for general populations such as primary care and other settings where bladder cancer prevalence is low;
Where available, describe variation in biomarker performance according to patient symptomatology (e.g. with micro (non-visible) or macro (visible) haematuria);
Classify existing biomarkers according to their sample source (e.g. urine, blood, breath or saliva) and molecular function (e.g. proteins, immunological markers, classic tumour markers, metabolomics, microRNAs, etc.)

Methodology

Comprehensive literature searches were conducted in MEDLINE and EMBASE from 1st January 2000 to June 2021 using the OVID interface. The search strategy included free-text terms and database specific subject headings – MESH terms for MEDLINE and Emtree terms for EMBASE – relating to each of the following areas: “bladder cancer”, “biomarker”, “diagnosis/detection”, “accuracy/performance”. Hand-searching of reference lists of included studies will also be performed.

The study selection process will comprise the following stages:

Assessment of titles and abstracts off all identified papers against the list of inclusion and exclusion criteria will be independently performed by at least two members of the review team. Studies clearly not relevant to the review will be rejected at this stage.
When a definite decision to reject a paper cannot be reached solely based on title and abstract, the full paper will be obtained for detailed assessment.
Full-text papers will be independently assessed by two members of the review team. Papers identified as not meeting the inclusion criteria by both researchers will be excluded. Disagreements will be resolved through discussion and consensus with other members of the review team.

Outputs & impact

Biomarkers that can be used to triage patients in primary care (for either monitoring or referring to specialist examinations) can be transformational. They can be particularly important for bladder cancer as there are no available screening programmes. Furthermore, the key predictive symptom (haematuria) is not always visible and not specific to bladder cancer. There is also evidence indicating missed opportunities for early diagnosis of bladder cancer after symptomatic presentation in primary care. This review can identify much needed evidence on which existing biomarkers have the potential to be used in primary care to facilitate assessment and GP decision-making.