Many companies and researchers have been working to develop non-invasive tests which could be used for both initial diagnosis of bladder cancer, and in follow up – to catch recurrences early.
A non-invasive test, used alongside cystoscopies, is something patients have been asking for; having one accurate enough to reduce the number of cystoscopies would represent a significant improvement for patients and great progress has been made towards that goal.
The information below is intended to help you to discuss with your urologist whether a non-invasive test using urinary biomarkers could play a role in the management of your cancer.
Urinary biomarkers – what are they?
Urinary biomarkers are chemicals produced by cancer cells that are in the urine (wee). If these chemicals are present in your wee it might be a sign that you have cancer. Researchers and companies have been working towards ensuring the biomarker testing is accurate enough to either detect bladder cancer initially (diagnose it) or detect that it has come back (its recurrence).
Types of urinary biomarkers (the technical bits)
Many chemicals are present in the wee of people with bladder cancer. These include particular proteins, as well as traces of DNA and mRNA. These chemicals are generally more plentiful in high-grade cancers and less plentiful in lower-grade cancers (Jur, RE et al, Urologic Oncology, 39(3))
Proteins: Proteins are complex molecules comprised of peptides, which are in turn comprised of amino acids. Proteins are involved in many functions including metabolism, movement, defence, cellular communication and molecular recognition.
DNA: DNA is an organic molecule found in the cell nucleus that codes the genetic information required for the transmission of inheritable traits.
mRNA: mRNA (messenger RNA) is a molecule that transfers information from DNA to the cell machinery that makes proteins.
How are urinary biomarkers tested for?
Urinary biomarkers are collected in samples of wee. The sample is then sent to a laboratory to be processed; it may take several days to get the result back. The result may be presented as a score or as a positive or negative result.
Some tests may be completed in the clinic (this is called near patient testing) with the result being rapidly available.
In evaluating the accuracy of tests, researchers measure their sensitivity and specificity.
- Sensitivity relates to how likely the test is to be positive in people with cancer. If the sensitivity is high, there will be very few negative tests in cancer patients, and this test can help to 'rule out' disease. If the sensitivity is low there will be many false negative tests.
- Specificity: if the test is positive, this relates to how likely you are to have cancer. If the specificity is high, a positive test likely means that cancer is present. If the specificity is low, there will be many false positive tests.
- A helpful example is urinary cytology, where a urine sample is examined in a laboratory for the presence of abnormal cells. If abnormal cells are present, then this is very likely to indicate the presence of bladder cancer and the test is said to have high specificity. However, the test is often negative in people with bladder cancer, and so the test is said to have low sensitivity. The low sensitivity limits the value of this test in 'ruling out' disease.
- Another term which can be used to describe the accuracy and usefulness of a test is Negative Predictive Value (NPV). This is the probability that a person with a negative screening test truly does not have cancer.
A perfect test (which does not exist) would have 100% sensitivity and 100% specificity but real-world tests never achieve this goal. Evaluating whether or not a urinary biomarker test is appropriate for you is personal to each bladder cancer patient and should be discussed with your urologist.
What are the advantages of urinary biomarkers?
- One advantage of urine biomarker tests is the fact that they are non-invasive and have no side effects.
- In general, urinary biomarkers have a high sensitivity and a high Negative Predictive Value. This means that a negative test very likely indicates no cancer present. This feature is helpful in the follow-up of non-muscle-invasive bladder cancer, when checking for early recurrences of the cancer.
- Using urinary biomarkers raises the prospect of reducing the number of cystoscopies required during follow-up. Although this benefit has yet to be demonstrated in large clinical trials, it has been estimated that there could be between 500-740 fewer cystoscopies needed per 1000 people.
- Some urinary biomarkers can potentially indicate the presence of upper urinary tract cancers in addition to bladder cancer.
- Urinary biomarkers are typically unaffected by the presence of blood in wee.
Are there disadvantages of urinary biomarkers?
- All tests for bladder cancer, including both cystoscopies and urinary biomarkers, may miss the cancer by giving a false negative result. The false negative rate for urinary biomarkers appears to be around 50 per 1000 people.
- Similarly, tests for bladder cancer, including both cystoscopies and urinary biomarkers, may give a false positive result, where the test is positive but no cancer is later found. The false positive rate for urinary biomarkers appears to be around 120 to 330 per 1000 people.
- Urinary biomarkers' unit costs vary from £60 to £300. However, the potential of urinary biomarkers to reduce the need for expensive and uncomfortable cystoscopies provides opportunities for possible cost savings.
- According to the European Association of Urologists (EAU), “The limitation of urinary cytology and current urinary markers is their low sensitivity for Lower-Grade recurrences’ (EAU 2023 guidelines)”
What is the current state of play?
Doctors in the UK look to various bodies for guidelines on clinical practice. In general, NHS England guidelines are followed by physicians in England, Wales and Northern Ireland whereas NHS Scotland issues guidelines for Scotland. Physicians also often consult the European Association of Urology (EAU) guidelines for bladder cancer.
Screening (in undiagnosed, symptom-free people)
Biomarker screening for bladder cancer is currently not recommended by NHS England, NHS Scotland or the European Association of Urology.
Diagnosis of bladder cancer
The NHS England guidelines for bladder cancer (written in 2015) state, ‘Offer white-light-guided Trans Urethral Removal of Bladder Tumour (TURBT) with one of photodynamic diagnosis, narrow-band imaging, cytology or a urinary biomarker test (such as UroVysion using in-situ fluorescence hybridisation [FISH], ImmunoCyt or a nuclear matrix protein 2022 [NMP22] test to people with suspected bladder cancer. This should be carried out or supervised by a urologist experienced in TURBT’.
Follow-up of bladder cancer
The European Association of Urology issued new guidelines in 2023 for the follow-up of low/intermediate risk non-muscle-invasive bladder cancer. Here's the relevant excerpt from the European Association of Urology guidelines:
‘To reduce the number of cystoscopy procedures, urinary markers should be able to detect recurrence before the tumours are large, numerous and muscle-invasive. The limitation of urinary cytology and current urinary markers is their low sensitivity for Lower-Grade recurrences.
According to current knowledge, no urinary marker can replace cystoscopy during follow-up or lower cystoscopy frequency in a routine fashion. One prospective randomised study found that knowledge of positive test results can improve the quality of follow-up cystoscopy, supporting the adjunctive role of a non-invasive urine test performed before follow-up cystoscopy.
Four of the promising and commercially available urine biomarkers, Cx-Bladder [Pacific Edge, New Zealand], ADX-Bladder [Arquer Diagnostics, UK], Xpert Bladder [Cepheid, USA] and EpiCheck [Nucleix, Israel], although not tested in randomised controlled trials, have such high sensitivities and negative predictive values in the referenced studies for High-Grade disease that these biomarkers may approach the sensitivity of cystoscopy. These 4 tests might be used to replace and/or postpone cystoscopy as they may identify the rare High-Grade recurrences occurring in low/intermediate Non-Muscle Invasive Bladder Cancer.’
NHS England is continually reviewing the evidence for urinary biomarkers. This has included ADX-Bladder in April 2019, Uro17 in February 2021 and Bladder Epicheck in May 2022. It is anticipated that further guidance on their use will be included in any updated guidelines.
What does this mean?
There is increasing interest in the potential role of urinary biomarkers in the management of bladder cancer:
Screening: There is ongoing research into using urinary biomarkers in routine screening for bladder cancer. However, NHS England and the European Association of Urology note that routine bladder cancer screening is not recommended.
Diagnosis: Both NHS England and the European Association of Urology agree that cystoscopy remains the key test in the diagnosis of bladder cancer. NHS England have identified 3 biomarkers that could be used alongside cystoscopy to assist in the diagnosis of bladder cancer and the European Association of Urology concurs noting that urinary biomarkers may help to identify missed tumours.
Surveillance/ follow-up: The European Association of Urology have identified 4 urinary biomarker tests with high Negative Predictive Values and high sensitivities. They have stated that these tests might be used to replace and/or postpone cystoscopy as they may identify the rare High-Grade recurrences occurring in low/intermediate non-muscle-invasive bladder cancer.
If you are undergoing follow-up for low/intermediate risk non-muscle-invasive bladder cancer you might wish to discuss the use of these urinary biomarker tests with your consultant urologist.
The following is relevant if urinary biomarkers are used to postpone and/or replace cystoscopy in the surveillance of low/intermediate risk non-muscle-invasive bladder cancer:
Although not currently recommended by NHS England or the European Association of Urologists, there is potential for urinary biomarkers to be used to postpone and/or replace cystoscopy in the surveillance of low/intermediate risk non-muscle-invasive bladder cancer.
- if there is a false positive result, you must have a cystoscopy. This doesn't increase your number of cystoscopies, but it means having a urinary biomarker test didn't avoid the cystoscopy. The disadvantages are that you will have spent money on the test (currently, this is not covered by the NHS) and there could be additional worry between the false positive test result and the cystoscopy confirming that the cancer has not returned.
- if there is a false negative result, the cancer will be able to grow for more time before being caught. You will need to weigh this risk versus the advantage of avoiding a cystoscopy. However, as noted by the European Association of Urologists, some biomarker tests have very good sensitivity for high-grade recurrences and therefore what might be missed with a false negative result would probably be a low-grade recurrence.
Comparison of the 4 urinary biomarkers mentioned by the European Association of Urology
The following table compares the 4 urinary biomarkers from the European Association of Urology guidelines. It is taken from the 2021 paper 'Diagnostic Accuracy of Novel Urinary Biomarker Tests in Non–muscle-invasive Bladder Cancer: A Systematic Review and Network Meta-analysis' by Ekaterina Laukhtina et al.
This meta-analysis, which analyses the data from several independent studies, includes the false positive and false negative rates expressed per 1000 patients with any grade of non-muscle invasive bladder cancer.
It also projects the number of cystoscopies that could be avoided (false negative plus true negative) and the number of unnecessary cystoscopies (false positive) that could result if urinary biomarkers were used to postpone and/or replace cystoscopies.
Table 1: Net benefits and interventions avoided for urinary biomarker tests to detect recurrence during the follow-up of 1,000 people with non-muscle-invasive bladder cancer (based on a pooled recurrence rate of 18%).
* Addenbrookes Hospital, Cambridge. James Cook University Hospital, Middlesbrough. New Cross Hospital, Wolverhampton. Ninewells Hospital, Dundee. Royal Bolton Hospital, Bolton. Royal Liverpool University, Liverpool. Royal Surrey County Hospital, Guilford. Information provided by the companies and deemed correct as at May 2023
Additionally, urinary biomarker tests may be offered to people in clinical trials. Recent trials have looked at blood markers (circulating cancer DNA) and urinary tests (the UroX and BladderPath studies). Details of current clinical trials in the UK can be found at: fightbladdercancer.co.uk/research-trials
The possible use of urinary biomarkers is a promising development for bladder cancer patients. The current European Association of Urologists guidelines suggest that they might be used for follow up (surveillance) of low/intermediate risk Non-Muscle-Invasive-Bladder- Cancer. Their use could reduce the number of follow up cystoscopies required; a real benefit for patients.
Each patient’s situation is different and we recommend that you discuss your individual situation and preferences with your clinicians to determine whether urinary biomarkers would be appropriate for your care.
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