The natural history of low grade Ta bladder cancer has been previously described by Rieken et al.1 who noted that in a retrospective analysis of 1,447 patients with low grade Ta the 5-year progression free survival rate was 95% and 5-year cancer specific survival rate was 98%. In this cohort, intermediate risk (versus low risk) was associated with higher risk of recurrence and progression, as well as worse cancer-specific mortality. Surveillance of low-risk bladder tumors varies slightly between the AUA, EAU, and NICE guidelines as depicted in the following table:
The case against surveillance cystoscopy is that it is costly and is both a burden to the patient and urologist. However, a recent study among 437 patients with bladder cancer found that nearly half (43%) of patients would not replace cystoscopy with a urinary biomarker unless it was 100% sensitive.2
Currently, according to Dr. Smith, there is a need for biomarkers to improve cystoscopy and potentially avoid cystoscopy. The EAU guidelines note that driven by the low sensitivity of urine cytology, numerous urinary tests have been developed, however none of these biomarkers have been accepted for diagnosis or follow-up in routine practice or clinical guidelines. Furthermore, the AUA guidelines note that in surveillance of non-muscle-invasive bladder cancer, a clinician should not use urinary biomarkers in place of cystoscopic evaluation and in a patient with a history of low-risk cancer and a normal cystoscopy, a clinician should not routinely use a urinary biomarker or cytology during surveillance.
Epigenetics provide the opportunity for developing biomarkers that take advantage of aberrant DNA methylation, histone modification, and non-coding RNAs. As such, several commercial biomarkers are now available. Cxbladder Monitor utilizes expression of IGFBP5, HOXA13, MDK, CDK1 and CXCR2 genes in voided urine plus clinical factors. This was designed as a rule out test with a sensitivity of 93% and NPV of 97%. It may be feasible to use this test to avoid cystoscopy in patients, as a positive marker does not mean cancer is present. Xpert Bladder Cancer Monitor is a 90-minute assay that uses five mRNAs (ABL1, CRH, IGF2, ANXA10, UPK1B) and in an independent test cohort this assay had an AUC of 0.87 (95% CI 0.81-0.92), with an overall sensitivity of 73% (63% for low grade tumors), specificity of 81%, and NPV of 93.9%. Bladder EpiCheck uses DNA methylation changes in a panel of 15 genomic biomarkers, providing a numerical EpiScore (0-100) that reflects the overall methylation level in the urine sample. An EpiScore >=60 is considered positive for bladder cancer with a sensitivity for low-grade tumors of 35%, sensitivity for high-grade tumors of 92%, and specificity of 86%.
With regards to treatment, the EAU guidelines state that in patients with a history of small, TaLG/G1 tumors, fulguration or laser vaporization of small papillary recurrences on an outpatient basis can reduce the therapeutic burden, however there are no prospective comparative studies assessing the oncological outcomes. The AUA guidelines state that in a patient with a history of low-grade Ta disease and a noted subcentimeter papillary tumor, a clinician may consider in-office fulguration as an alternative to resection under anesthesia (Expert Opinion). In a systematic review assessing active surveillance for non-muscle-invasive bladder cancer there were 6 studies cumulating 403 patients, including patients from two prospective trials [3]. This systematic review reported a reclassification rate of 65% (15% based on grade and 10% on stage) with 2% of patients progressing to MIBC, and with a large proportion of patients eventually going on to TURBT. Additional studies suggest that after initial diagnosis of low-grade Ta tumors, subsequent stable, low-grade appearing recurrences can be managed conservatively with office cystoscopy and fulguration or even followed using an active surveillance protocol.
The OPTIMA II prospective, single-arm, open label, phase 2 clinical trial was designed to evaluate the efficacy and safety of UGN-102 for nonsurgical chemoablation in patients with low-grade non-muscle-invasive bladder cancer. The trial design of OPTIMA II is as follows:
The trial was initially presented at the AUA in 2020. The primary endpoint for OPTIMA II was complete response at 3 months, which was experienced in 65% of patients (95% CI 52-77%), with estimated durability of response at 12 months of 60%.
Dr. Smith concluded her presentation of deintensifying follow-up for patients with low-grade bladder tumors with the following take-home messages:
- Deintensification of low grade non-muscle invasive bladder cancer is needed
- Strategies include: reducing cystoscopic surveillance and/or replacing/alternating cystoscopy with biomarkers
- Surveillance for low-grade tumors
Presented by: Angela B. Smith, MD, Vice-Chair Of Academic Affairs, Director Of Urologic Oncology, Associate Professor Of Urology, University of North Carolina, Chapel Hill, NC
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021
References:
- Rieken M, Xylinas E, Kluth L, et al. Long-term cancer-specific outcomes of TaG1 urothelial carcinoma of the bladder. Eur Urol2014 Jan;65(1):201-209.
- Van Osch FHM, Nekeman D, Aaronson NK, et al. Patients choose certainty over burden in bladder cancer surveillance. World J Urol. 2019 Dec;37(12):2747-2753.
- Marcq G, Henon F, Ouzaid I, et al. Active surveillance for non-muscle invasive bladder cancer. Transl Androl Urol. 2019 Feb;8(1):54-60.