Learning Objectives

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

• Implement current practice guidelines into the office setting.
• Identify the best intravesical agent and duration of therapy for low, intermediate, and high-risk settings and what to do during a BCG shortage.
• Identify methods to treat significant toxicities from various intravesical therapies.
• Define high risk scenarios that necessitate cystectomy and options for BCG-unresponsive disease.
• Discuss the scientific rationale for investigating immune oncology agents for BCG unresponsive disease and become familiar with current clinical trial designs.

Transurethral resection of a bladder tumor (TURBT) is the first step in bladder cancer management for both new and recurrent tumors. For urologists, it a highly rewarding procedure as it cures most patients with non-muscle-invasive bladder cancer (NMIBC) and provides valuable prognostic information. Detailed characterization of the cystoscopic findings and a complete visual TURBT is imperative to outcomes and this cannot be overemphasized. Studies confirm implementing a surgical checklist during the performance of a TURBT as well as surgeons receiving serial feedback on key quality indicators, such as the presence of muscularis propria in the pathology specimen, are strategies that can lead to better quality TURBT. A procedure checklist that includes recording number of tumors, largest tumor size, tumor configuration, presence of carcinoma in situ (CIS), direct visualization of including muscularis propria in the resection and confirming complete TURBT led to better quality care and the desired result of lower tumor recurrence rates.¹

After the initial TURBT, knowing which patients benefit from a repeat TURBT within 6 weeks adds to the overall quality of the completeness of TURBT improves staging and very likely reduces tumor recurrence. A visually incomplete initial TURBT is an indication for repeat complete TURBT, if feasible. Other indications for repeat TURBT include T1 bladder cancer, high-grade Ta bladder cancer of large volume or if muscularis propria was not present and if bladder preservation in a patient with variant histology is planned. If the equipment is available, use of enhanced cystoscopy, such as blue light, during TURBT also improves quality of TURBT and reduces recurrence rates.

A visually complete TURBT provides greatest confidence in assigning NMIBC patients as low, intermediate or high risk of disease recurrence and progression. The AUA NMIBC guideline places emphasis on tumor grade and stage, tumor size, presence of CIS, whether the tumor is recurrent, variant histology, lymphovascular invasion, prostatic urethral involvement and response to bacillus Calmette-Guérin (BCG) as criteria needed to assign NMIBC risk group. By assigning a risk group decisions whether to administer single-dose perioperative intravescial chemotherapy (SPI), induction and maintenance intravesical therapy become clear and evidence based. All low risk (low grade, <3 cm, solitary Ta tumor) and some intermediate risk NMIBC patients benefit from SPI (EORTC [European Organization for the Treatment of Cancer] risk score <5). Intravesical gemcitabine is becoming the standard of care for SPI because of less toxicity and lower cost but mitomycin remains an option and importantly in the low-risk group no further intravesical therapy is recommended following SPI.²

Intermediate risk (low grade Ta tumor >3 cm or multifocal or recurrent) patients represent a heterogeneous population and is the largest group of NMIBC. Almost all patients in this category benefit from a 6-week course of induction chemotherapy (ie mitomycin or gemcitabine) or BCG. For intermediate risk patients, maintenance intravesical therapy should be considered for up to 1 year especially if BCG was used for induction. Maintenance chemotherapy is administered once monthly and BCG thrice weekly at 3, 6 and 12 months. Intravesical chemotherapy is best for patients with a lower probability of tumor recurrence because of similar efficacy, lower toxicity and greater drug availability when compared to BCG. In the intermediate risk category, 4 factors including only 1 tumor, tumor size <3 cm, no recurrence in the past year and low frequency of recurrence over time help select patients for chemotherapy with a lower probability of tumor recurrence.³ However, if a patient received prior induction chemotherapy and develops a tumor recurrence these recurrences should be treated with intravesical BCG and vice versa regardless of prognostic factors for tumor recurrence.

Patients diagnosed with high-risk NMIBC (high-grade tumors, CIS or T1) benefit little from SPI but they should receive induction and maintenance BCG for 3 years as it known to reduce cancer recurrence and progression. Unfortunately this is not always possible as there is a national BCG shortage, so risk-adapted strategies are needed to conserve the drug for those who need it most. Guidance of what to do during a BCG shortage has been provided by various organizations and authors and an important consideration when comparing patients who received 1 year vs 3 years of maintenance BCG was no difference in cancer progression or cancer-specific mortality. The only benefit was lower cancer recurrence rates in patients receiving 3 years of maintenance.⁴ This finding along with other findings is applicable during a BCG shortage as 1 year of maintenance, receiving 2 instead of 3 doses of BCG and receiving a half to a third dose BCG if 1 vial can be shared amongst patients need to be strongly considered to conserve a highly valuable resource in short supply. These recommendations are unlikely to lead to higher rates of tumor progression but are certainly associated with higher rates of tumor recurrence. During a BCG shortage, intermediate risk patients should only be treated with intravesical chemotherapy.

BCG is a great story of success in the field of urology and has cured or preserved the bladders of millions of people worldwide. Nevertheless, BCG is not an effective therapy for all patients diagnosed with high-risk NMIBC and these individuals are better managed by up-front radical cystectomy before disease progression. Individuals at greatest risk for progression to muscle-invasive bladder cancer include T1 bladder cancer with concurrent multifocal CIS or lymphovascular invasion or variant histology (ie sarcomatoid, plasmacytoid, micropapillary, neuroendocrine). The presence of multifocal T1 bladder cancer, concurrent prostatic urethral involvement and T1 disease on repeat TURBT are other indications to consider up-front radical cystectomy for NMIBC. Radical cystectomy in a surgically fit patient is always appropriate for high-risk NMIBC if not removing the bladder would present a loss of an opportunity to cure the patient.

Maintenance BCG is highly effective at reducing cancer recurrence rates as well as disease progression in high-risk NMIBC. However, up to 20% of patients at high risk will develop muscle-invasive bladder cancer during followup, and the majority of these patients were expected to respond well to BCG and not offered up-front radical cystectomy. At the present time we do not have the ability to determine which cancers are likely to respond to BCG from those that are resistant to the treatment. Nevertheless, based on our current knowledge it is vitally important to develop an understanding of when continuing to administer further intravesical BCG is not in the best interest of the patient. This state of disease has been recently characterized as BCG-unresponsive and evolved from a collaborative effort between clinicians with expertise in the field of bladder cancer and the FDA (U.S. Food and Drug Administration; FDA-guidance document 2018). Following exposure to an adequate course of intravesical BCG and dependent upon whether a complete response was achieved or if the cancer recurred after a disease-free state various states of high-risk NMIBC have been defined including BCG-refractory, BCG early or late relapsing and BCG intolerant. These newly accepted definitions are dependent upon patients receiving an adequate course of BCG defined as 5 of 6 doses of induction BCG plus at least 2 additional doses of BCG (as part of re-induction or maintenance) within 6 months of starting treatment. BCG-refractory disease (presence of T1 bladder cancer at 3 months after induction BCG or persistent high-grade disease at 6 months despite adequate BCG) or BCG-early relapsing disease (recurrence of high-grade disease within 6–12 months after achieving a disease-free state after adequate BCG) are included in the category of BCG-unresponsive disease. This denotes a subgroup of patients at highest risk of disease recurrence and progression for whom additional BCG is not a feasible option. If the patient is deemed ineligible or refuses radical cystectomy for BCG-unresponsive disease they should be considered for a number of single-arm clinical trials currently enrolling patients in this disease space. A recently closed trial, KEYNOTE 057, led to the approval of intravenous pembrolizumab for BCG-unresponsive CIS with or without papillary tumors with an overall 1-year response rate of about 20%.⁵ Other options to consider for BCG-unresponsive disease include the more favored combination (gemcitabine and docetaxol) as opposed to single agent (ie gemcitabine, docetaxol, mitomycin) intravesical chemotherapies and possibly, if approval is granted, other investigational agents currently under review by the FDA (ie nadofaragene firadenovec and oportuzumab monatox).