The American Urological Association periodically charges a taskforce of content experts to review and update existing practice guidelines. In 2016 the nonmuscle invasive bladder cancer (NMIBC) guideline was reviewed, and at that time a brand-new practice guideline was completed for muscle invasive bladder cancer (MIBC).¹ Last year, based on the rapid pace of change in the field of bladder cancer, the AUA had each of these guidelines reviewed for relevant content updates. Working with the Agency for Healthcare Research Quality (AHRQ), a group of experts reviewed the most recent literature in the field of NMIBC and MIBC and updated each guideline accordingly.

For the NMIBC guideline, the updated AHRQ search identified 1,626 relevant new publications, of which 76 met inclusion criteria for review by the committee. The committee recommended a significant guideline change for the management of bacillus Calmette-Guérin (BCG) unresponsive bladder cancer. In early 2020 the U.S. Food and Drug Administration (FDA) approved systemic pembrolizumab for the treatment of BCG unresponsive carcinoma in situ (CIS) for patients who refuse or are ineligible for radical cystectomy.² This approval was based on the findings from KEYNOTE-057; a multicenter, open-label, single-arm, phase II trial of pembrolizumab for BCG unresponsive CIS. This trial demonstrated an initial response rate of 41% and a durable response rate of 21% at 1 year. The NMIBC guidelines now include the option to use systemic pembrolizumab for BCG unresponsive CIS in patients that are ineligible or refuse radical cystectomy.³ This recommendation was considered an expert opinion, as there was no peer reviewed manuscript published at the time of the update for committee review. The efficacy seen in this trial led the committee to suggest that there remains a significant unmet need for more effective agents in this area. Non-FDA approved but commonly utilized salvage chemotherapy regimens were also listed as options for the management of BCG unresponsive disease, including gemcitabine, docetaxel and combinations of these agents.

Guideline Statement 15 was amended to include gemcitabine as an option for immediate postoperative chemotherapy. In 2018, a randomized trial of an immediate postoperative dose of gemcitabine (2 g/100 cc saline) compared to saline for patients with suspected low grade NMIBC demonstrated a relative risk reduction in recurrence of 35% with gemcitabine.⁴ Given the favorable toxicity profile, the committee recommended consideration of gemcitabine for patients being given an immediate postoperative dose of chemotherapy.

No guideline statement was changed in the area of urinary biomarkers and their role in the management of NMIBC. However, additional review and discussion of the new urinary biomarker panel known as Cxbladder Monitor led to an updated discussion of its use in NMIBC surveillance. Cxbladder Monitor has been shown to have a 93% sensitivity and 97% negative predictive value for recurrent NMIBC. Although it was found to outperform several commonly used biomarkers, it did not meet recommendations for use in lieu of standard cystoscopic surveillance in patients capable of undergoing cystoscopy. The notable limitations of Cxbladder Monitor are its poor sensitivity to detect low-risk recurrences and the concern for low specificity.

The panel acknowledged the ongoing international BCG shortage and referred practitioners to the 2019 AUA statement on guidance during the BCG crisis. This statement includes several management strategies to maintain high quality care for patients with NMIBC. These recommendations may supersede several of the NMIBC guidelines statements that apply to intravesical BCG.

In the area of MIBC, the updated literature search from 2016 to 2020 identified 2,005 relevant publications, of which 38 met inclusion criteria for consideration by the committee.

There were several minor modifications made to this guideline, including the recommended extent of surgical resection during a female radical cystectomy. The indications for resection of the vaginal wall, uterus and ovaries were discussed in order to emphasize that preservation of these organs may be considered in well-selected patients if negative surgical margins can be ensured. This updated content is based on retrospective cohort studies, and surgeons must ultimately decide whether gynecologic organ-preserving cystectomy is safe for their patients on an individual basis. In regards to the management of patients following neoadjuvant chemotherapy, the modified guideline now states that radical cystectomy should ideally be performed within 12 weeks of completion of the neoadjuvant chemotherapy.

The review of these two critical guidelines reinforced that the majority of existing guideline recommendations were confirmed to be correct, as only minor modifications were made for each guideline. The committee identified several areas of research to improve care in the future, including the role of biomarkers, more effective options for BCG unresponsive disease in NMIBC, integration of systemic immunotherapy in the treatment of MIBC and improved protocols for bladder preservation in MIBC.