Learning Objective

At the conclusion of the activity, participants will be able to:

• Explain the 2020 amendments to the SUO/AUA Non-Muscle-Invasive Bladder Cancer and Muscle-Invasive Bladder Cancer Guidelines, including what to do if bacillus Calmette-Guérin (BCG) is unavailable.

At the 2021 American Urological Association annual meeting the AUA/SUO non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) guidelines were reviewed in a plenary session.¹ In 2020, 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 Health Research Quality (AHRQ), a group of experts reviewed the most recent literature in the field of NMIBC and MIBC and updated each guideline accordingly. These updates were presented and several existing guidelines were emphasized in the plenary session.

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 Since that time the KEYNOTE-057 trial, a multicenter, open-label, single-arm, phase II trial of pembrolizumab for BCG unresponsive CIS, was published in The Lancet Oncology.³ This trial demonstrated an initial response rate of 41%, a durable response rate of 21% at 1 year, with 11% remaining disease-free beyond 2 years. The NMIBC guidelines now include the option to use systemic pembrolizumab for BCG unresponsive CIS in patients who are ineligible or refuse radical cystectomy. 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. NonFDA 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 gm/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.

The topic of urinary biomarkers was discussed, and additional review and discussion of the new urinary biomarker panel known as Cxbladder™ Monitor and its role 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 session also discussed the ongoing international BCG shortage and reviewed 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 supersede several of the NMIBC guidelines statements that apply to intravesical BCG.

In addition, the guideline statements stressing pathological review in the setting of variant histology, definition of BCG unresponsive state, the surveillance schedule for low risk patients, and the use of fluorescent cystoscopy were all discussed. No changes were made in these guidelines.

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 anterior 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 in each individual patient. 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 neoadjuvant chemotherapy.

Several existing guidelines that did not undergo revision were reviewed during the plenary session. The recommendation that cisplatin based multiagent chemotherapy is the standard of care in the neoadjuvant setting and the specific recommendation that carboplatin should not be used as a neoadjuvant therapy were stressed. In addition, the guideline covering organ preservation stresses that maximal debulking transurethral resection of bladder tumor be performed and that radiotherapy alone in the absence of systemic therapy is not supported by the guidelines.

The review of these 2 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.