Patients with newly diagnosed high-risk NMIBC have a 60-70% chance of recurrence and a 10-45% chance of progression to muscle-invasive or metastatic bladder cancer within 5 years.37 Multiple studies and meta-analyses have shown that a six-week induction course of BCG decreases the risk of recurrence.205-208 In further analysis performed for this systematic review, BCG was shown to be superior in the prevention of recurrence (3 trials; RR: 0.56; 95% CI: 0.43 to 0.71; I2=0%) and progression (4 trials; RR: 0.39; 95% CI: 0.24 to 0.64; I2=40%) compared to no intravesical therapy.114 BCG was superior to doxorubicin (2 trials; RR: 0.31, 95% CI: 0.16 to 0.61; and RR: 0.75, 95% CI: 0.64 to 0.88), epirubicin (5 trials; RR: 0.54; 95% CI: 0.40 to 0.74; I2=76%), and mitomycin (when BCG maintenance is added to induction [5 trials; RR: 0.79; 95% CI: 0.71 to 0.87; I2=0%]) in the prevention of recurrence.114 There is insufficient evidence to recommend one particular strain of BCG: BCG is a heterogeneous organism with at least eight different strains being used for intravesical therapy worldwide.209 Although there is insufficient evidence to recommend one strain over another, several small studies suggest that different strains may have different efficacies. For instance, one study of patients with NMIBC comparing the two most commonly used strains in the U.S. (BCG Tice® versus BCG Connaught) reported that a 6-week course of BCG Connaught resulted in a significantly better recurrence-free survival (74.0%; 95% CI: 62.8 to 87.2) compared to BCG Tice® (48.0%; 95% CI: 35.5 to 65.1; p=0.0108). However, there was no difference in progression-free survival.210 SWOG S1602 recently reported results of a trial examining the use of TICE® versus Tokyo-172 strains of BCG in addition to intradermal priming. The results, which were reported at the American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, demonstrated that Tokyo-172 was non-inferior to TICE® BCG. In addition, intradermal priming did not show a significant benefit (<a href="https://clinicaltrials.gov/study/NCT03091660">https://clinicaltrials.gov/study/NCT03091660</a>). Another small study conducted by Herr et al. examined the use of “double induction BCG” without maintenance therapy in primary or recurrent NMIBC. In this phase 2 trial of 76 patients, the complete response rate was 91% at 6 months and the recurrence-free survival at 2 years was 85%.211  There is insufficient evidence to prescribe a particular strength of BCG: Seven trials have compared standard-dose BCG to reduced-dose BCG given as a variety of different strains, in various combinations and permutations. Most trials found no clear difference between standard-dose and reduced-dose BCG in terms of recurrence and other outcomes.114 In favor of standard-dose BCG, a meta-analysis by Zhu et al. demonstrated improved recurrence-free survival with standard-dose compared to reduced-dose (hazard ratio [HR]: 1.162; 95% CI: 1.051 to 1.285; P=0.003), but no difference in progression-free survival (HR: 1.151; 95% CI: 0.853 to 1.554; P=0.356).212 The largest individual study of 1,355 patients (EORTC-30962) compared different BCG strengths (full-dose versus 1/3-dose) and different BCG maintenance schedules (1 year versus 3 years), and found no difference in recurrence-free survival between 1/3-dose and full-dose administered for either 1 year or 3 years. However, in high-risk patients (patients with high-grade, T1 tumors), the 3-year full-dose schedule had an improved recurrence-free survival (HR: 1.61; 95% CI: 1.13 to 2.30; p=0.009) compared to the 1-year 1/3-dose schedule, leading the authors to recommend full-dose BCG in this patient subgroup (EORTC-30962 was not formally powered to test this hypothesis).213 In most studies, dose reduction was associated with a decreased risk of local and systemic side effects.114 However, in this study there was no difference in the risk of local or systemic side effects or in the discontinuation rate between full-dose and 1/3-dose BCG.213 Importantly, it should be noted, EORTC-30962 did not include patients with CIS. There is rapidly evolving evidence examining the use of BCG in combination with a variety of other agents as well as alternative regimens in the BCG naïve patient. A number of trials have examined the use of BCG in combination with a variety of agents including sasanlimab, durvalumab, and mitomycin C. In the CREST trial, a prospective randomized trial, the authors examined the addition of subcutaneous sasanlimab plus BCG and maintenance to BCG induction alone, to BCG induction plus maintenance.214 The study demonstrated that the addition of sasanlimab with BCG induction and maintenance was superior to BCG induction and maintenance (HR: 0.68). As expected, there were more adverse events in the sasanlimab plus BCG group (29% Grades 3-4 adverse events versus 6% in BCG).214 Similarly, a randomized trial of durvalumab plus BCG and maintenance versus BCG induction and maintenance was performed in the POTOMAC trial, a randomized phase 3 trial. This trial evaluated the addition of intravenous durvalumab to intravesical BCG. This study demonstrated that at a median follow-up of 60.7 months, there was a 32% reduction in the risk of recurrent high-grade disease with the addition of durvalumab. However, 21% of the durvalumab plus BCG and maintenance group experienced Grades 3-4 adverse events versus only 4% in the BCG group.215 Neither of these studies have demonstrated statistically significant improvements in progression, CSS, or overall survival and concerns about the potential serious adverse effects associated with systemic immunotherapy continue to exist. There have been several studies examining the addition of mitomycin to BCG in BCG naïve patients. In 2015, a study was published suggesting that the combination of BCG plus mitomycin was more effective yet more toxic than BCG alone.216 However, a recently published randomized trial (ANZUP 1301) found no difference when mitomycin was added to BCG in terms of preventing recurrence but did find that this regimen required fewer doses of BCG and fewer treatment discontinuations.217, 218 Sequential intravesical gemcitabine and docetaxel have been evaluated in a prospective phase 2 trial where 25 patients who were BCG naïve received intravesical gemcitabine and docetaxel weekly for 6 weeks.219 The trial reported a 100% complete response rate at 3 months and recurrence-free survival of 92% at 12 months. Finally, a retrospective cohort study examining gemcitabine plus docetaxel given sequentially versus BCG for high-risk NMIBC demonstrated that the recurrence-free survival rate was 76%, 71%, and 69% at 6, 12, and 24 months, respectively, in the BCG alone group. In the docetaxel and gemcitabine group, the recurrence-free survival was 92%, 85%, and 81% at 6, 12, and 24 months, respectively. Ongoing RCTs are currently being conducted to further explore this option.220 Patients with higher-risk features such as persistent high-grade T1 disease on repeat resection, T1 tumors with associated CIS, LVI presence, or subtype histologies should be offered radical cystectomy as an alternative to BCG.