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Use of Bladder Epicheck® in the Follow-up of High-Risk Non-Muscle-Invasive Bladder Cancer: A Systematic Literature Review - Beyond the Abstract

In recent years, various urinary biomarkers have emerged with the aim of reducing or potentially replacing the number of cystoscopies (standard of care) required for the follow-up of non-muscle invasive bladder cancer (NMIBC). These biomarkers have shown high sensitivity (Se) and negative predictive value (NPV) for detecting high-grade (HG) recurrences, though their performance is more limited for low-grade (LG) recurrences. However, their integration into routine clinical practice has not yet been standardized.1

In the manuscript published in Actas Urológicas Españolas,2 our group has conducted a systematic literature review on the use of Bladder Epicheck® and its current clinical utility in monitoring and detecting NMIBC recurrences. Bladder Epicheck® assesses DNA methylation changes using a panel of 15 genomic biomarkers from voided urine samples, with an EpiScore™ greater than 60 considered indicative of a positive result. Importantly, its principal value lies in the high NPV for HG NMIBC.3

The review was based on bibliographic searches in the PubMed, Web of Science, and Scopus databases up until October 2023. Inclusion criteria included a history of NMIBC with no restrictions on histological grade or risk group, and a comparison of biomarker results with white light cystoscopy, histology, and/or cytology. Notably, the use of the biomarker in the management of upper urinary tract tumors (UTUC) was considered an exclusion criterion.

Eighty-seven percent (87%) of the studies analyzed (n=15) were prospective, involving a total of 3761 patients under follow-up for NMIBC. Of these patients, 53.2% had previously received intravesical instillations, including 62.5% with Bacillus Calmette-Guérin (BCG), 27% with mitomycin C, 6.7% with both agents and 1% with another type of intravesical treatment.

The mean Se for recurrence detection was 88% for HG and 45% for LG. The weighted mean Se, specificity (Sp), positive predictive value (PPV), and NPV were 71.6%, 84.5%, 56.4%, and 92.8%, respectively. The NPV was notably higher for non-LG cases, close to 98%. The area under curve (AUC) obtained was 85.6%.

Given its high NPV, various monitoring schemes have been proposed that alternate between cystoscopy and Bladder Epicheck®.4,5 Our group suggests the scheme depicted in Figure 1 for monitoring high-risk (HR) NMIBC.5 This subgroup may benefit from a greater economic impact and improvement in quality of life by reducing the number of invasive test (cystoscopies) required, particularly during the initial years of follow-up.

We recommend conducting an imaging test (CT urography, or ultrasound if CT is unavailable) at control points where cystoscopy is not performed (Figure 1). This should be done alongside the biomarker check-up to enhance sensitivity further and minimize diagnostic delays.

Performing joint urine cytology could be controversial; however, we believe it is appropriate to maintain it in the follow-up protocol due to its low cost, non-invasive nature, and high Sp in HG cases and CIS (Figure 1). In cases with either negative or positive cytology, cytology alone might be sufficient. However, in NMIBC cases with atypical or suspicious cytology, Pierconti et al6 suggest that combining Bladder Epicheck® with urine cytology could reduce the number of required cystoscopies. Additionally, various studies indicate that the results of the biomarker are not influenced by previous bladder instillations, unlike urine cytology, which may be affected.3,7


Figure 1. 5-Year Follow-up Scheme for HR-NMIBC Alternating Cystoscopy and Bladder Epicheck®. CT: computed tomography; IVU: intravenous urography; US: ultrasonography; m: months.

In cases where a positive Bladder Epicheck® is obtained, we propose the diagnostic algorithm shown in Figure 2 to rule out urothelial recurrence, similar to protocols followed for positive cytology results.2 Given its moderate PPV, false positives are not uncommon. However, there is a significant correlation between increased EpiScore™ levels and the frequency of HG recurrence during follow-up. Consequently, based on our experience, in instances where recurrence is not detected after initial investigation, it is crucial to conduct close follow-up, particularly in cases with an EpiScore™ ≥80.

Diagnostic_algorithm_for_positive_Bladder_Epicheck.png
Figure 2. Diagnostic Algorithm for Positive Bladder Epicheck®

Our conclusions:

  • Bladder Epicheck® has proven to be a valuable urinary biomarker in the NMIBC follow-up.
  • Its primary utility is evident in high-risk NMIBC cases (Figure 1), where it can significantly reduce the number of cystoscopies required during follow-up. This reduction potentially enhances patient quality of life and has a favorable economic impact.
  • In instances of a positive Bladder Epicheck® result, we propose the diagnostic algorithm depicted in Figure 2 to effectively rule out urothelial recurrence.
Written by: Caño Velasco, Jorge;1 Artero Fullana, Silvia;1 Polanco Pujol, Lucía;1 Lafuente Puentedura, Alfonso;1 Subiela, José Daniel;2 Aragón Chamizo, Juan;1 Moralejo Gárate, Mercedes;1 Hernández Fernández, Carlos1

  1. Urology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
  2. Urology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
References:

  1. Gontero P, Birtle A, Compérat E, Dominguez Escrig J.L, Liedberg F, Mariappan P, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). 2024. [Accessed June 2024].
  2. Caño Velasco J, Artero Fullana S, Polanco Pujol L, Lafuente Puentedura A, Subiela JD, Aragón Chamizo J, et al. Use of Bladder Epicheck® in the follow-up of high-risk non-muscle-invasive Bladder cancer: A systematic literature review. Actas Urol Esp (Engl Ed). 2024 May 10:S2173-5786(24)00064-7.
  3. D’Andrea, F. Soria, S. Zehetmayer, K.M. Gust, S. Korn, J.A. Witjes, et al. Diagnostic accuracy, clinical utility and influence on decision-making of a methylation urine biomarker test in the surveillance of non-muscle-invasive bladder cancer. BJU Int. 2019; 123:959-67.
  4. Hekman MCH, Wijn SRW, Lotan Y, Govers TM, Witjes JA. Bladder EpiCheck urine test in the follow-up of NMIBC: a cost analysis. World J Urol. 2023 Feb;41(2):471-476.
  5. Caño Velasco J, Polanco Pujol L, Moreno Cortés JC, Lafuente Puentedura A, Hernández Fernández C. Bladder Epicheck® for surveillance in high-risk non-muscle-invasive bladder cancer: initial experience and follow-up proposal. Actas Urol Esp (Engl Ed). 2023 Oct;47(8):471-473.
  6. Pierconti F, Martini M, Fiorentino V, Cenci T, Capodimonti S, Straccia P, et al. The combination cytology/epichek test in non muscle invasive bladder carcinoma follow-up: Effective tool or useless expence? Urol Oncol. 2021 Feb;39(2):131.e17-131.e21.
  7. Ragonese M, Gianfrancesco LD, Palermo G, Pierconti F, Martini M, Foti M, et al. The Role of Bladder Epicheck Test In Follow-Up of Patients with Non-Muscle Invasive Bladder Cancer. Clin Genitourin Cancer. 2022 Aug;20(4):e271-e275.
  8. Pierconti F, Rossi ED, Cenci T, Carlino A, Fiorentino V, Totaro A, et al. DNA methylation analysis in urinary samples: A useful method to predict the risk of neoplastic recurrence in patients with urothelial carcinoma of the bladder in the high-risk group. Cancer Cytopathol. 2023 Mar;131(3):158-164.
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