There is data showing that even in newly presenting patients with bladder cancer, urologists appear to reliably predict lower grade and muscle-invasive disease.1 This helps to appropriately and efficiently use the available technology and select patients for clinical trials.
However, in follow-up, Dr. Witjes believes that cystoscopy should be replaced by urinary biomarkers. This is because too many cystoscopies are probably done in follow-up, it is a costly procedure, it causes patient and urologist burden, and the tools currently being used are not optimal.
In a large study from the VA system, cystoscopy overuse occurred in 75% of patients with an excess of 1846 more cystoscopies performed than recommended. Overuse was shown to be associated with patient race, two comorbidities, and earlier year of diagnosis.2 This raises concerns about cost and quality.
In a study analyzing the cost of cystoscopy using a Markov model, the cumulative costs for a 5-year period were 52,$125, 146,$250, and 366,$143 for low-, intermediate-, and high-risk disease, respectively. 71-92% were done due to progression and 8% due to recurrence.3
Cystoscopic evaluation causes a significant burden on the patients as well. Data have shown that 89% of patients prefer flexible ureteroscopy if the test sensitivity is less than 90%, and 75% would accept a urine test as a replacement for cystoscopy, only if it was capable of detecting >95% of recurrences. Patients demand a marker that is sensitive as cystoscopy before willing to forego cystoscopy for bladder cancer surveillance.4
Importantly, there is a high rate of missed lesions in cystoscopy, with 62% of CIS lesions missed using white light cystoscopy, and 29% of CIS patients (integrated results from PDD studies).
In a large systematic review assessing urinary cytology in 36 studies with over 14200 patients, the sensitivity of cytology was only 44% with a specificity of 96%.
In summary, we do too much, of low quality and with a low level of evidence, certainly in low-grade NMIBC. But there are realistic alternatives that need to be discussed. Dr. Witjes began describing some older biomarkers. The first one described was the FISH biomarker, which detects aneuploidy of chromosome 3, 7 and 17, and loss of 9p21. It utilizes a very expensive technique, and in a systematic review of 14 studies with 2960 patients, the sensitivity was shown to be 76% with a specificity of 85%.
Next, NMP22 was discussed. This is a nuclear matrix protein released after cell death. It has been shown that tumor cells have 80 times higher NMP22 concentration than non-tumor cells. Elevated NMP22 has been associated with bladder cancer. In a systematic review of 41 studies with almost 14000 patients, the sensitivity was shown to be 68% and specificity of 79%.
There are some important practical issues to consider with the use of urinary biomarkers. Benign conditions, such as infections, and previous BCG instillations will influence many urinary markers. The clinical context in which the marker is used is extremely important. To date, the EAU 2020 guidelines do not recommend the use of urinary biomarkers.
Epigenetics is the external or environmental factors that switch genes on and off and affect how cells read genes without altering the underlying DNA sequence. This field can be used for the creation of biomarkers to identify cancer development, progression, and impact on therapy. There are three categories of biomarkers of this type:
- Aberrant DNA methylation (hyper or hypomethylation)
- Histone modification
- Non-coding RNA’s
The Xpert Bladder cancer monitor includes five mRNA targets: ABL1, CRH, IGF2, UPK1B, and ANXA10. This assay is performed in a self-contained cartridge using GeneXpert systems (Cepheid) with a turnaround time of 90 minutes. It has been shown to have a negative predictive value (NPV) of 93% and 97.6% in all bladder tumors and high-grade tumors, respectively.5
Another new urine-based hypermethylation biomarker is the Bladder EpiCheck test for surveillance of NMIBC. It is a real-time PCR test using more than ten cc of urine. It uses 15 proprietary DNA methylation markers to find bladder cancer. It gives a number between 0-100, calculated by a software algorithm, representing the overall methylation level of the sample test. A score of over 60 is considered positive. It has been shown to have a negative predictive value of 99.3% overall, and 95.1% for non-low grade Ta recurrence6. It is not influenced by infections or previous intravesical instillation therapy, and the score increases with a higher stage and grade.
There are additional tests that include the Cxbladder, which is a urinary mRNA plus phenotypic information. It has been shown to have an NPV of 97%. Another test is the ADXBLADDER-MCM5, which is a novel biomarker of growth, harboring an NPV of 93%. Lastly, Uromonitor-V2, which assess gene alterations (TERT, FGFR3, KRAS), has shown an NPV of 95.3%.
Dr. Witjes concluded his talk stating that the current state of follow-up in bladder cancer is not evidence-based, inconvenient, and causes a high workload and cost. There is a need for a urinary biomarker to replace cystoscopies, but the bar for such a biomarker is quite high. As of today, epigenetics is a promising and evolving field for use to create urinary biomarkers. For the use in follow-up, there are several available biomarkers that have a ~99% NPV for non-low-grade recurrences. Alternating cystoscopy and cytology with these novel biomarkers could reduce the current diagnostic burden.
Presented by: J. Alfred Witjes, MD, PhD, Department Urology, Radboud University Medical Centre, Nujmegen, Netherleands
Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHanan at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020.
- Mariappan P, Lavin V, Phua CQ, Khan SAA, Donat R, Smith G. Predicting Grade and Stage at Cystoscopy in Newly Presenting Bladder Cancers-a Prospective Double-Blind Clinical Study. Urology 2017; 109: 134-9.
- Han DS, Lynch KE, Chang JW, et al. Overuse of Cystoscopic Surveillance Among Patients With Low-risk Non-Muscle-invasive Bladder Cancer - A National Study of Patient, Provider, and Facility Factors. Urology 2019; 131: 112-9.
- Mossanen M, Wang Y, Szymaniak J, et al. Evaluating the cost of surveillance for non-muscle-invasive bladder cancer: an analysis based on risk categories. World journal of urology 2019; 37(10): 2059-65.
- van Osch FHM, Nekeman D, Aaronson NK, et al. Patients choose certainty over burden in bladder cancer surveillance. World journal of urology 2019; 37(12): 2747-53.
- Valenberg F, Hiar AM, Wallace E, et al. Prospective Validation of an mRNA-based Urine Test for Surveillance of Patients with Bladder Cancer. European urology 2019; 75(5): 853-60.
- Witjes JA, Morote J, Cornel EB, et al. Performance of the Bladder EpiCheck™ Methylation Test for Patients Under Surveillance for Non-muscle-invasive Bladder Cancer: Results of a Multicenter, Prospective, Blinded Clinical Trial. European urology oncology 2018; 1(4): 307-13.